Familial Adenomatous Polyposis

MONDO:0021056 Pathograph 8 Show in embeddings browser hereditary cancer-predisposing syndrome

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in the APC tumor suppressor gene. It is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, with virtually 100% lifetime risk of colorectal cancer if untreated. FAP exemplifies the adenoma-carcinoma sequence and the role of Wnt/β-catenin pathway dysregulation in colorectal tumorigenesis. Extracolonic manifestations include desmoid tumors, duodenal adenomas, osteomas (Gardner syndrome), and congenital hypertrophy of the retinal pigment epithelium (CHRPE).

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6
Pathophys.
6
Phenotypes
1
Hypotheses
3
Gaps
8
Pathograph
1
Genes
4
Medical Actions
3
Subtypes
2
Datasets
9
References
1
Deep Research
1
Hyp. Reports
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Subtypes

3
Classic FAP
Characterized by >100 colorectal adenomatous polyps, typically appearing in adolescence with polyposis by age 20-30. Without prophylactic colectomy, colorectal cancer develops by age 40 on average. Caused by mutations in the mutation cluster region (MCR) of APC.
Show evidence (1 reference)
PMID:28668823 SUPPORT Human Clinical
"It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
Establishes the classic FAP phenotype as hundreds of colonic polyps with high malignant transformation potential.
Attenuated FAP (AFAP)
Milder phenotype with fewer polyps (10-100), later onset of polyposis, right-sided colon predominance, and delayed colorectal cancer risk (average age 50-55). Associated with mutations at the 5' or 3' ends of APC or in the alternatively spliced region of exon 9.
Gardner Syndrome
FAP variant with prominent extracolonic manifestations including osteomas (especially mandible and skull), epidermoid cysts, desmoid tumors, and dental abnormalities. Historically considered separate but now recognized as FAP with variable expressivity.
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Mechanistic Hypotheses

1
Canonical APC / Wnt-β-Catenin / Polyp-to-Carcinoma Model
canonical_apc_wnt_betacatenin_polyp_carcinoma_model CANONICAL
Evidence balance 5 support 1 refute
Familial adenomatous polyposis (FAP) is caused by germline heterozygous loss-of-function variants in APC on 5q22.2 encoding the adenomatous polyposis coli tumor suppressor. APC normally serves as a scaffold in the β-catenin destruction complex (with Axin, GSK-3β, CK1) targeting β-catenin for ubiquitin-proteasomal degradation. Biallelic APC inactivation (germline + somatic 'second hit') stabilizes cytoplasmic β-catenin, allowing nuclear translocation and TCF/LEF-dependent transcription of pro-proliferative targets (MYC, CCND1, LGR5), initiating colorectal adenoma formation throughout the colon. Sequential acquisition of KRAS, TP53, and SMAD4 mutations follows the Vogelstein adenoma-carcinoma progression model, producing virtually 100% CRC risk by age 40 in classic FAP without intervention. Prophylactic colectomy is the standard of care; mouse Apc^Min/+ models recapitulate intestinal polyposis and validate the Wnt-axis as the canonical initiating lesion.
Retained as CANONICAL with mechanistic qualifications. The 2026 openscientist hypothesis-search report (kb/hypotheses/Familial_Adenomatous_Polyposis/canonical_apc_wnt_betacatenin_polyp_carcinoma_model) finds SUPPORTED. The core APC-loss → β-catenin stabilization → TCF/LEF-dependent proliferation → adenoma cascade is validated by biochemical reconstitution, near-100% untreated lifetime CRC risk, Apc^Min/+ mouse polyposis, and convergent APC/CTNNB1 mutations in extracolonic tumors (desmoids, thyroid, salivary). Three qualifications: (1) the 'just-right' signaling model — second APC hits are non-randomly selected to produce OPTIMAL (not maximal) Wnt activation; truncating mutations after the SAMP-repeats are favored, producing intermediate β-catenin levels that maximize transformation; (2) APC has Wnt-independent tumor-suppressive functions including chromosomal instability regulation, DNA replication control, and cytoskeletal/microtubule regulation, explaining why complete APC loss often differs from CTNNB1 activation; (3) some colorectal cancer contexts show lack of correlation between APC mutation and β-catenin nuclear localization, challenging the assumption that Wnt activation is the sole mechanistic output of APC loss (documented in early-onset sporadic rectal cancer rather than in FAP adenomas; see the discussions entry). ClinGen's Hereditary Cancer Gene Curation Expert Panel classifies the APC gene-disease relationship with classic or attenuated FAP as Definitive; the separate ClinGen InSiGHT Variant Curation Expert Panel maintains APC-specific ACMG/AMP criteria for classifying individual germline variants. These are different products and the second does not establish the first.
Deep research
OpenScientist citations 51 citations 2026-05-24T17:21:40.882783
Show evidence (6 references)
PMID:28668823 SUPPORT Other
"It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
Existing canonical mechanism citation in the dismech knowledge base, used as the seed for the hypothesis-search deep-research run.
PMID:34352208 SUPPORT In Vitro
"We reveal that AXIN1 polymerization and APC promote β-catenin capture, phosphorylation, and ubiquitylation."
Reconstitution of the human destruction complex from purified components grounds the scaffolding role this hypothesis assigns to APC at the biochemical level, independent of cellular context.
PMID:34352208 SUPPORT In Vitro
"Oncogenic APC truncation variants, although part of the complex, are functionally impaired."
The truncating alleles that cause FAP still assemble into the destruction complex but cannot perform its function, which is the molecular form the loss-of-function step of this hypothesis takes.
+ 3 more references
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Discussions and Knowledge Gaps

3
Does APC inactivation invariably produce nuclear β-catenin accumulation in FAP adenomas, or can APC loss drive tumorigenesis with transcriptional Wnt output decoupled from β-catenin nuclear localization?
KNOWLEDGE GAP OPEN apc_beta_catenin_nuclear_localization_discordance
Attached to
pathophysiology#Wnt/β-Catenin Pathway Activation
The edge from APC loss to nuclear β-catenin is the load-bearing step of the canonical model, and it has been reported not to hold. Bala et al. found no correlation between APC mutation and β-catenin nuclear localization on serial sections of the same tumour regions, and could not explain the discordance by KRAS status; the result reproduced in colorectal cancer cell lines carrying various APC mutations. The scope limit matters: those samples are early-onset sporadic rectal cancers, not FAP adenomas, so the gap is whether the same decoupling occurs in the germline-APC setting this entry models. Spatial heterogeneity of Wnt output within a tumour could explain part of the finding as an immunohistochemistry sampling artefact, but has not been shown to explain all of it. If the decoupling is real in FAP, then nuclear β-catenin is an unreliable pharmacodynamic readout for Wnt-directed intervention, and part of APC's tumour-initiating function runs through some other output.
Proposed experiments
Single-cell β-catenin dynamics after acute APC deletion in FAP organoids
exp_fap_acute_apc_deletion_beta_catenin_dynamics
Induce acute biallelic APC deletion with inducible Cre in patient-derived intestinal organoids from FAP carriers and from non-carrier controls, then track β-catenin subcellular localization, TCF/LEF transcriptional output, and cell fate at single-cell resolution over roughly two weeks. Read nuclear β-catenin by immunocytochemistry against Wnt target gene expression by single-cell RNA sequencing in the same cells, and score a chromosomal instability marker in parallel so a discordant cell can be checked for the alternative APC output.
Would support
pathophysiology#Wnt/β-Catenin Pathway Activation
Supporting outcome
  • APC deletion is followed in essentially every transformed cell by nuclear β-catenin accumulation together with matching TCF/LEF target induction, making the reported discordance an artefact of fixed-tissue sampling or of the sporadic rectal cancer context.
Refuting outcome
  • A reproducible subpopulation shows Wnt target induction without nuclear β-catenin, or transformation without either, identifying conditions under which the canonical APC to nuclear β-catenin link does not hold in cells of FAP origin.
Raised from the 2026 openscientist hypothesis-search report, whose Gap 1 flags this as the highest-impact challenge to the canonical model. The assessment sidecar qualifies the claim on scope (sporadic early-onset rectal cancer, not FAP).
Show evidence (1 reference)
PMID:36586069 SUPPORT Human Clinical
"The lack of correlation was validated in CRC cell lines harboring various APC mutations."
Establishes that the discordance survives in a controlled cell-line setting rather than being a property of one tissue series, which is what makes it a knowledge gap rather than a sampling complaint.
How much of APC's tumour-suppressive function in FAP is carried by Wnt regulation and how much by its role in chromosome segregation, and does that balance differ between adenoma initiation and progression to carcinoma?
KNOWLEDGE GAP OPEN wnt_versus_chromosomal_instability_contribution
Attached to
pathophysiology#APC-Driven Chromosomal Instability pathophysiology#Wnt/β-Catenin Pathway Activation
Both arms are established individually. APC loss deregulates β-catenin, and separately produces chromosome and spindle aberrations through sequences lying C-terminal to the β-catenin regulatory domain. What has not been done is a separation-of-function experiment that quantifies their relative contributions, so the entry carries two parallel edges out of APC loss without being able to weight them. This is not an academic point: if instability contributes materially to initiation rather than only to progression, an intervention that normalises Wnt output would leave part of the mechanism running.
Proposed experiments
Separation-of-function APC alleles in intestinal organoids
exp_apc_separation_of_function_alleles
Engineer APC variants that retain β-catenin regulation but lose the kinetochore-associated function, and the converse, then express each in Apc-null intestinal organoids. Score adenoma-like outgrowth, karyotype stability, and progression kinetics as separate outcomes rather than as a single transformation endpoint.
Would support
pathophysiology#APC-Driven Chromosomal Instability
Supporting outcome
  • A Wnt-competent but instability-deficient APC allele fails to suppress transformation fully, showing that chromosome segregation control is a non-redundant part of APC tumour suppression.
Refuting outcome
  • A Wnt-competent APC allele suppresses outgrowth as completely as wild-type APC regardless of its effect on segregation, placing the instability arm downstream of, or incidental to, Wnt deregulation in this setting.
Raised from the 2026 openscientist hypothesis-search report Gap 2. The supporting sources for the instability arm itself are cited on the pathophysiology node; nothing is cited here because the gap is precisely that the comparative experiment has not been reported.
Which human genetic modifiers account for the variation in polyp burden and age at diagnosis seen among FAP patients carrying the same APC variant?
KNOWLEDGE GAP OPEN human_fap_polyp_burden_modifier_genes
Attached to
phenotypes#Colorectal Polyposis
Mouse work established that background genotype alone changes adenoma multiplicity several fold at a fixed Apc mutation, so modifiers are real in principle, and intrafamilial variability in FAP families sharing one APC variant says they are likely real in patients. The human loci are unidentified. The mouse candidate that came closest, Pla2g2a at the Mom1 locus, did not transfer: human studies did not confirm PLA2G2A as a major modifier because the relevant functional polymorphism does not exist in humans. Until human modifiers are known, APC genotype is the only stratifier available for deciding surveillance intensity and the timing of prophylactic surgery, and it does not explain the observed spread.
Proposed experiments
Modifier GWAS across FAP registries stratified by APC genotype
exp_fap_modifier_gwas
Assemble more than 500 genetically confirmed FAP patients across national polyposis registries, use cumulative polyp burden and age at first adenoma as quantitative phenotypes, and adjust for APC variant position so that the known genotype effect does not absorb the modifier signal.
Would support
phenotypes#Colorectal Polyposis
Supporting outcome
  • Replicating modifier loci reach significance for polyp burden independently of APC variant position, giving a stratifier that APC genotype alone does not provide.
Refuting outcome
  • No locus reaches significance at adequate power, indicating the residual variation is environmental, stochastic, or driven by rare variants that a common-variant scan cannot see.
Raised from the 2026 openscientist hypothesis-search report Gap 4. The assessment sidecar qualifies that report's attribution of the mouse effect to Mom1/Pla2g2a. Missing spaces in the quoted snippet are an artefact of the cached full text and are reproduced verbatim.
Show evidence (1 reference)
PMID:15710876 SUPPORT Model Organism
"Unfortunately, studies in humans did not confirmPLA2G2Aas a major modifier of colorectal cancer risk in humans because functional polymorphic variation did not exist"
Records the failure of the leading mouse modifier candidate to transfer to humans, which is what leaves the human modifier question open. Note the quoted sentence comes from the paper's own account of prior work; the study itself attributes its 3-to-5-fold multiplicity difference to a locus near Apc or to structural variation on chromosome 18, not to Mom1/Pla2g2a.
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Pathophysiology

6
APC Tumor Suppressor Loss
Germline heterozygous APC mutations result in one functional allele. Somatic loss or mutation of the remaining wild-type allele (second hit) eliminates APC function, initiating adenoma formation. This follows Knudson's two-hit hypothesis for tumor suppressor gene inactivation.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology. LGR5+ intestinal crypt stem cell CL:0002250 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves LGR5+ intestinal crypt stem cell, annotated with intestinal crypt stem cell (CL:0002250). CL:0002250 is a cell type from the Cell Ontology.
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Wnt/β-Catenin Pathway Activation APC loss prevents β-catenin degradation
APC-Driven Chromosomal Instability Loss of the APC sequences C-terminal to the β-catenin regulatory domain disrupts kinetochore-microtubule attachment, a tumour-suppressive function that is separate from Wnt regulation.
Show evidence (3 references)
PMID:28668823 SUPPORT
"In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
Confirms that FAP follows the two-hit mechanism for both colorectal cancer and desmoid tumor development.
PMID:19092804 SUPPORT Model Organism
"Here we show that deletion of Apc in these stem cells leads to their transformation within days."
Lineage tracing in Lgr5-CreER mice establishes the long-lived crypt stem cell as the cell in which APC loss initiates neoplasia, which is why this node is annotated with the crypt stem cell as well as the generic intestinal epithelial cell.
PMID:19092804 SUPPORT Model Organism
"When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls."
The negative arm of the same experiment: APC loss in transit-amplifying cells does not sustain adenoma growth, so the initiating step is restricted to the stem cell compartment rather than being a general epithelial effect.
APC-Driven Chromosomal Instability
APC accumulates at the kinetochore during mitosis and is required for efficient microtubule attachment. Truncating alleles that remove the APC sequences C-terminal to the β-catenin regulatory domain produce chromosome and spindle aberrations, so APC loss drives aneuploidy through a route that does not pass through β-catenin. This parallel arm is thought to accelerate the accumulation of the additional driver lesions required for adenomas to become carcinomas, and it is the reason Wnt-directed intervention alone may not capture the whole consequence of APC loss.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
chromosome segregation GO:0007059 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromosome segregation (GO:0007059). GO:0007059 is a biological process from the Gene Ontology.
Downstream
Colorectal Cancer Progression Aneuploidy accelerates acquisition of the additional driver mutations that convert adenomas to invasive carcinoma.
Show evidence (2 references)
PMID:11283620 SUPPORT In Vitro
"Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation."
Direct genetic evidence that APC loss disrupts chromosome segregation, establishing this node as a consequence of APC inactivation rather than of Wnt pathway output.
PMID:11283620 SUPPORT In Vitro
"Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores."
Names the specific mitotic defect behind the instability, and pairs with the report that APC accumulates at the kinetochore during mitosis.
Wnt/β-Catenin Pathway Activation
APC normally functions in the destruction complex (with Axin, GSK3β, CK1) to phosphorylate β-catenin, targeting it for ubiquitination and proteasomal degradation. Loss of APC allows β-catenin to accumulate, translocate to the nucleus, and activate Wnt target genes driving proliferation.
Wnt signaling pathway GO:0016055 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology.
Downstream
Uncontrolled Intestinal Epithelial Proliferation β-catenin activates proliferative and stemness genes
Show evidence (1 reference)
PMID:28668823 SUPPORT Human Clinical
"germline mutations affect the functional domains of the APC gene that are responsible for interactions of the transcript with β-catenin"
Confirms that pathogenic APC variants disrupt the APC–β-catenin interaction domains, the molecular basis for Wnt pathway dysregulation downstream of APC loss.
Uncontrolled Intestinal Epithelial Proliferation
Nuclear β-catenin activates TCF/LEF transcription factors, driving expression of Wnt target genes including MYC, CCND1 (cyclin D1), and others that promote cell cycle progression. This results in uncontrolled proliferation of intestinal crypt cells, forming adenomatous polyps.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Downstream
Adenoma Formation Hyperproliferative epithelium forms adenomatous polyps
Adenoma Formation
Sustained Wnt pathway activation drives adenoma development. Adenomas are benign neoplasms but represent the first step in the adenoma-carcinoma sequence. In FAP, hundreds to thousands of adenomas develop, dramatically increasing the probability that one will progress to carcinoma.
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology. rectum UBERON:0001052 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in rectum (UBERON:0001052). UBERON:0001052 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Colorectal Polyposis Wnt-driven intestinal epithelial adenoma formation produces the hundreds of colonic polyps that define FAP.
Colorectal Cancer Progression Accumulated mutations drive adenoma-to-carcinoma progression
Show evidence (1 reference)
PMID:28668823 SUPPORT Human Clinical
"It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
Hundreds of colonic adenomas with high transformation potential is the defining FAP feature that drives near-certain malignant progression.
Colorectal Cancer Progression
Adenomas acquire additional mutations in KRAS, TP53, SMAD4, and other genes through the adenoma-carcinoma sequence. In FAP, the large number of adenomas makes it virtually certain that at least one will progress to invasive adenocarcinoma without intervention.
cell population proliferation GO:0008283 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Downstream
Colorectal Cancer APC two-hit progression in FAP adenomas drives colorectal cancer development.
Show evidence (1 reference)
PMID:28668823 SUPPORT Human Clinical
"In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
Two-hit inactivation of APC is the critical molecular step in FAP-driven colorectal cancer development.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Adenomatous Polyposis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Digestive 3
Colorectal Polyposis OBLIGATE Large intestinal polyposis HP:0030255 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large intestinal polyposis (HP:0030255). HP:0030255 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28668823 SUPPORT Human Clinical
"It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
The defining FAP phenotype is the presence of hundreds of colonic adenomatous polyps.
Colorectal Cancer VERY_FREQUENT Colon cancer HP:0003003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colon cancer (HP:0003003). HP:0003003 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28668823 SUPPORT Human Clinical
"In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
Colorectal cancer is the principal malignant outcome of FAP, driven by two-hit APC inactivation.
PMID:37853284 SUPPORT Human Clinical
"The risk of stage II-IV CRC was estimated to increase markedly at the age of 49 years in the Genotype-1 patients and 34 years in the Genotype-2 patients, respectively."
Source for the genotype-dependent timing sentence added above. Genotype-1 is defined in this study as variants in attenuated-FAP-associated regions and Genotype-2 as all others, so the 34-versus-49 split is a genotype effect on when to intervene, not on whether cancer eventually occurs. Bounds worth keeping in view: 171 patients in a retrospective Japanese multicentre registry, and the inflection is specific to stage II-IV disease.
Duodenal Adenomas VERY_FREQUENT Small intestinal polyposis HP:0030256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small intestinal polyposis (HP:0030256). HP:0030256 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1055/a-2011-1933 SUPPORT Human Clinical
"Nearly all patients with FAP will also develop adenomas in the duodenum, but only 4 % to 10 % duodenal cancer"
Confirms duodenal adenomas develop in nearly all FAP patients, though only a minority progress to duodenal cancer.
DOI:10.1055/a-2011-1933 SUPPORT Human Clinical
"Duodenal cancer generally has a poor prognosis and is one of the most common FAP-related causes of death"
Supports duodenal/ampullary cancer as a leading cause of death in FAP patients.
Eye 1
Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) Abnormal retinal pigmentation HP:0007703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of retinal pigmentation, annotated with Abnormal retinal pigmentation (HP:0007703). HP:0007703 is a phenotype from the Human Phenotype Ontology.
Frequency band omitted: the cited GeneReviews source describes extracolonic manifestations as "variably present" without a quantitative frequency, which supports the disease-phenotype association but not a FrequencyEnum band (see docs/frequency-evidence-guidelines.md).
Show evidence (1 reference)
PMID:20301519 SUPPORT Human Clinical
"Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE)"
GeneReviews lists CHRPE among the extracolonic manifestations of FAP.
Musculoskeletal 1
Osteomas HP:0100246 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoma (HP:0100246). HP:0100246 is a phenotype from the Human Phenotype Ontology.
Frequency band omitted: the cited GeneReviews source describes extracolonic manifestations as "variably present" without a quantitative frequency, which supports the disease-phenotype association but not a FrequencyEnum band (see docs/frequency-evidence-guidelines.md).
Show evidence (1 reference)
PMID:20301519 SUPPORT Human Clinical
"Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities"
GeneReviews lists osteomas among the extracolonic manifestations of FAP.
Neoplasm 1
Desmoid Tumors FREQUENT HP:6001034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Desmoid tumor (HP:6001034). HP:6001034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28668823 SUPPORT
"Among associated lesions in FAP, desmoid tumors represent a common possible life-threatening condition that requires special attention. They are rare tumors occurring with a particularly high incidence in FAP, especially after surgery."
Review confirms desmoid tumors are a serious complication of FAP with particularly high incidence after abdominal surgery.
🧬

Genetic Associations

1
APC (Germline Loss-of-Function Mutations)
Gene: APC hgnc:583 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is APC (hgnc:583). hgnc:583 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Dominant
Show evidence (6 references)
PMID:28668823 SUPPORT
"Several lines of evidence show that germline mutations affect the functional domains of the APC gene that are responsible for interactions of the transcript with β-catenin, whereas somatic second mutations involve the downstream region of the gene."
Supports APC domain involvement and second-hit pattern, but does not fully cover all detailed genotype-phenotype and de novo rate claims in this entry.
PMID:18433509 SUPPORT Human Clinical
"Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017)."
Substantiates the mutation-cluster-region genotype-phenotype claim asserted in the notes above, in 96 unrelated families from the Swedish Polyposis Registry. The same series reports dense polyposis (>1000 adenomas) in 75% of severe versus 30% of non-severe genotypes.
PMID:40237877 SUPPORT Human Clinical
"APC somatic (postzygotic) mosaicism can be identified in up to 50% of unexplained adenomatous polyposis cases."
Source for the mosaicism sentence added to the notes above. Mosaicism extends APC's causal role to polyposis that germline testing scores as mutation negative, which changes both the testing strategy and the risk assessment offered to relatives.
+ 3 more references
💊

Medical Actions

4
Prophylactic Colectomy
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical removal of the colon is the primary management to prevent colorectal cancer. Options include total proctocolectomy with ileal pouch-anal anastomosis (IPAA) or subtotal colectomy with ileorectal anastomosis (IRA). Timing is typically in late teens/early twenties or when polyp burden becomes unmanageable endoscopically.
Show evidence (1 reference)
PMID:20301519 SUPPORT Human Clinical
"Colectomy to reduce the risk for CRC in individuals with classic FAP"
GeneReviews recommends colectomy as the standard measure to prevent colorectal cancer in classic FAP.
Endoscopic Surveillance
Action: colonoscopyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is colonoscopy (NCIT:C16450). NCIT:C16450 is a clinical intervention from the NCI Thesaurus. Ontology label: Colonoscopy NCIT:C16450
Colonoscopy every one to two years beginning at age 10-15 years in at-risk individuals with classic FAP (late adolescence in attenuated FAP) to detect polyp development. Esophagogastroduodenoscopy with visualization of the ampulla of Vater by age 20-25 years or prior to colon surgery, with duodenal adenoma burden graded by Spigelman stage. Surveillance of rectal stump or pouch after colectomy.
Show evidence (2 references)
PMID:20301519 SUPPORT Human Clinical
"Colorectal screening by colonoscopy every one to two years beginning at age ten to 15 years for classic FAP and in late adolescence for attenuated FAP"
GeneReviews specifies the colonoscopy surveillance interval and starting age for classic and attenuated FAP.
PMID:20301519 SUPPORT Human Clinical
"esophagogastroduodenoscopy with visualization of the ampulla of Vater by age 20 to 25 years or prior to colon surgery, with consideration of complete small bowel visualization in the setting of advanced Spigelman stage"
GeneReviews specifies the upper-endoscopy surveillance recommendation, including ampullary visualization and the role of Spigelman stage.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling and testing for at-risk family members. Children of affected parents have 50% risk. Predictive testing allows targeted surveillance in mutation carriers and reassurance for non-carriers.
Show evidence (2 references)
PMID:20301519 SUPPORT Human Clinical
"Molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant"
GeneReviews supports genetic testing of at-risk relatives to guide surveillance and reassure non-carriers.
PMID:20301519 SUPPORT Human Clinical
"Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant in APC."
GeneReviews states the 50% offspring recurrence risk that this counseling recommendation is built on.
Chemoprevention
Action: chemopreventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemoprevention, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: sulindac CHEBI:9352 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sulindac (CHEBI:9352). CHEBI:9352 is a therapeutic agent from Chemical Entities of Biological Interest. celecoxib CHEBI:41423 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses celecoxib (CHEBI:41423). CHEBI:41423 is a therapeutic agent from Chemical Entities of Biological Interest.
Sulindac and celecoxib (COX-2 inhibitors) have demonstrated ability to reduce polyp number and size but do not eliminate cancer risk. Used as adjunct to surveillance, not as alternative to surgery.
Show evidence (1 reference)
PMID:20301519 SUPPORT Human Clinical
"Several studies have shown that NSAIDs and erlotinib have caused regression of adenomas and decreased the polyp burden in individuals with FAP, though there are currently no FDA-approved chemopreventive agents for FAP"
GeneReviews notes NSAID-class chemoprevention reduces polyp burden but is not FDA-approved as a cancer-risk-modifying therapy in FAP.
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Biochemical Markers

1
APC Genetic Testing
📊

Related Datasets

2
Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis ega:EGAS00001003598
Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Familial Adenomatous Polyposis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
APC Promoter Deletion in Classic Familial Adenomatous Polyposis dbgap:phs000904
The ~80% of individuals with classic familial adenomatous polyposis (FAP) have detectable mutations in the coding sequence of the adenomatous polyposis coli (APC) gene. To investigate the 20% of families without detectable causative mutations, we used exome sequencing and second-generation sequencing of the APC locus including non-coding regions. We identified a novel ~11kb deletion 44kb upstream of APC that was present only in affected individuals of three kindreds.
Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Familial Adenomatous Polyposis"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Familial Adenomatous Polyposis
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary cancer
  syndrome caused by germline pathogenic variants in the APC tumor suppressor gene.
  It is characterized by the development of hundreds to thousands of adenomatous
  polyps in the colon and rectum, with virtually 100% lifetime risk of colorectal
  cancer if untreated. FAP exemplifies the adenoma-carcinoma sequence and the role
  of Wnt/β-catenin pathway dysregulation in colorectal tumorigenesis. Extracolonic
  manifestations include desmoid tumors, duodenal adenomas, osteomas (Gardner syndrome),
  and congenital hypertrophy of the retinal pigment epithelium (CHRPE).
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Polyposis Syndrome
parents:
- hereditary cancer-predisposing syndrome
has_subtypes:
- name: Classic FAP
  description: >-
    Characterized by >100 colorectal adenomatous polyps, typically appearing in
    adolescence with polyposis by age 20-30. Without prophylactic colectomy,
    colorectal cancer develops by age 40 on average. Caused by mutations in the
    mutation cluster region (MCR) of APC.
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
    explanation: >-
      Establishes the classic FAP phenotype as hundreds of colonic polyps
      with high malignant transformation potential.
- name: Attenuated FAP (AFAP)
  description: >-
    Milder phenotype with fewer polyps (10-100), later onset of polyposis,
    right-sided colon predominance, and delayed colorectal cancer risk (average
    age 50-55). Associated with mutations at the 5' or 3' ends of APC or in
    the alternatively spliced region of exon 9.
- name: Gardner Syndrome
  description: >-
    FAP variant with prominent extracolonic manifestations including osteomas
    (especially mandible and skull), epidermoid cysts, desmoid tumors, and
    dental abnormalities. Historically considered separate but now recognized
    as FAP with variable expressivity.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_apc_wnt_betacatenin_polyp_carcinoma_model
  hypothesis_label: Canonical APC / Wnt-β-Catenin / Polyp-to-Carcinoma Model
  status: CANONICAL
  description: >-
    Familial adenomatous polyposis (FAP) is caused by germline heterozygous loss-of-function variants in
    APC on 5q22.2 encoding the adenomatous polyposis coli tumor suppressor. APC normally serves as a
    scaffold in the β-catenin destruction complex (with Axin, GSK-3β, CK1) targeting β-catenin for
    ubiquitin-proteasomal degradation. Biallelic APC inactivation (germline + somatic 'second hit')
    stabilizes cytoplasmic β-catenin, allowing nuclear translocation and TCF/LEF-dependent transcription
    of pro-proliferative targets (MYC, CCND1, LGR5), initiating colorectal adenoma formation throughout
    the colon. Sequential acquisition of KRAS, TP53, and SMAD4 mutations follows the Vogelstein adenoma-carcinoma
    progression model, producing virtually 100% CRC risk by age 40 in classic FAP without
    intervention. Prophylactic colectomy is the standard of care; mouse Apc^Min/+ models recapitulate
    intestinal polyposis and validate the Wnt-axis as the canonical initiating lesion.
  notes: >-
    Retained as CANONICAL with mechanistic qualifications.
    The 2026 openscientist hypothesis-search report
    (kb/hypotheses/Familial_Adenomatous_Polyposis/canonical_apc_wnt_betacatenin_polyp_carcinoma_model)
    finds SUPPORTED. The core APC-loss → β-catenin
    stabilization → TCF/LEF-dependent proliferation → adenoma
    cascade is validated by biochemical reconstitution, near-100%
    untreated lifetime CRC risk, Apc^Min/+ mouse polyposis, and
    convergent APC/CTNNB1 mutations in extracolonic tumors
    (desmoids, thyroid, salivary). Three qualifications: (1) the
    'just-right' signaling model — second APC hits are non-randomly
    selected to produce OPTIMAL (not maximal) Wnt
    activation; truncating mutations after the SAMP-repeats are
    favored, producing intermediate β-catenin levels that maximize
    transformation; (2) APC has Wnt-independent tumor-suppressive
    functions including chromosomal instability regulation, DNA
    replication control, and cytoskeletal/microtubule regulation,
    explaining why complete APC loss often differs from CTNNB1
    activation; (3) some colorectal cancer contexts show lack of
    correlation between APC mutation and β-catenin nuclear
    localization, challenging the assumption that Wnt activation
    is the sole mechanistic output of APC loss (documented in
    early-onset sporadic rectal cancer rather than in FAP
    adenomas; see the discussions entry). ClinGen's Hereditary
    Cancer Gene Curation Expert Panel classifies the APC gene-disease
    relationship with classic or attenuated FAP as Definitive; the
    separate ClinGen InSiGHT Variant Curation Expert Panel maintains
    APC-specific ACMG/AMP criteria for classifying individual germline
    variants. These are different products and the second does not
    establish the first.
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
    explanation: >
      Existing canonical mechanism citation in the dismech
      knowledge base, used as the seed for the hypothesis-search
      deep-research run.
  - reference: PMID:34352208
    reference_title: >-
      Reconstitution of the destruction complex defines roles of AXIN polymers and
      APC in β-catenin capture, phosphorylation, and ubiquitylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We reveal that AXIN1 polymerization and APC promote β-catenin capture, phosphorylation, and ubiquitylation."
    explanation: >-
      Reconstitution of the human destruction complex from purified components
      grounds the scaffolding role this hypothesis assigns to APC at the
      biochemical level, independent of cellular context.
  - reference: PMID:34352208
    reference_title: >-
      Reconstitution of the destruction complex defines roles of AXIN polymers and
      APC in β-catenin capture, phosphorylation, and ubiquitylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Oncogenic APC truncation variants, although part of the complex, are functionally impaired."
    explanation: >-
      The truncating alleles that cause FAP still assemble into the destruction
      complex but cannot perform its function, which is the molecular form the
      loss-of-function step of this hypothesis takes.
  - reference: PMID:12045208
    reference_title: >-
      The 'just-right' signaling model: APC somatic mutations are selected based on
      a specific level of activation of the beta-catenin signaling cascade.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that this selection process is aimed at a specific degree of beta-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the beta-catenin downregulating motifs in APC."
    explanation: >-
      Analysis of 133 adenomas from six FAP patients is the primary source for the
      just-right qualification recorded in the notes above: second hits are
      co-selected for an intermediate rather than a maximal level of β-catenin
      signalling, so complete APC inactivation is not what tumours select for.
  - reference: PMID:11283620
    reference_title: Mutations in the APC tumour suppressor gene cause chromosomal instability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that loss of APC sequences that lie C-terminal to the beta-catenin regulatory domain contributes to chromosomal instability in colorectal cancer."
    explanation: >-
      Primary source for the second qualification in the notes above: the APC
      sequences whose loss drives chromosomal instability lie outside the
      β-catenin regulatory domain, so this arm of APC tumour suppression does not
      run through Wnt signalling.
  - reference: PMID:36586069
    reference_title: >-
      To β or Not to β: Lack of Correlation Between APC Mutation and β-Catenin
      Nuclear Localization in Colorectal Cancer.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we provide evidence for a surprising lack of correlation between APC mutation and β-catenin nuclear localization in early-onset sporadic rectal cancer samples."
    explanation: >-
      Cuts against the hypothesis's assumption that APC inactivation invariably
      produces nuclear β-catenin. It qualifies rather than overturns the model:
      the series is early-onset sporadic rectal cancer, not FAP adenomas, and the
      discordance is reported by a single group with cell-line validation.
pathophysiology:
- name: APC Tumor Suppressor Loss
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  description: >-
    Germline heterozygous APC mutations result in one functional allele. Somatic
    loss or mutation of the remaining wild-type allele (second hit) eliminates
    APC function, initiating adenoma formation. This follows Knudson's two-hit
    hypothesis for tumor suppressor gene inactivation.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: LGR5+ intestinal crypt stem cell
    term:
      id: CL:0002250
      label: intestinal crypt stem cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  downstream:
  - target: Wnt/β-Catenin Pathway Activation
    description: APC loss prevents β-catenin degradation
  - target: APC-Driven Chromosomal Instability
    causal_link_type: DIRECT
    description: >-
      Loss of the APC sequences C-terminal to the β-catenin regulatory domain
      disrupts kinetochore-microtubule attachment, a tumour-suppressive function
      that is separate from Wnt regulation.
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    snippet: >-
      In agreement with Knudson's 'two-hit' theory, the inactivation of the residual
      APC gene in FAP is a critical step in the development of both colorectal
      cancer and desmoids.
    explanation: >-
      Confirms that FAP follows the two-hit mechanism for both colorectal cancer
      and desmoid tumor development.
  - reference: PMID:19092804
    reference_title: Crypt stem cells as the cells-of-origin of intestinal cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that deletion of Apc in these stem cells leads to their \ntransformation within days."
    explanation: >-
      Lineage tracing in Lgr5-CreER mice establishes the long-lived crypt stem cell
      as the cell in which APC loss initiates neoplasia, which is why this node is
      annotated with the crypt stem cell as well as the generic intestinal
      epithelial cell.
  - reference: PMID:19092804
    reference_title: Crypt stem cells as the cells-of-origin of intestinal cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "When Apc is deleted in short-lived transit-amplifying cells using a different \ncre mouse, the growth of the induced microadenomas rapidly stalls."
    explanation: >-
      The negative arm of the same experiment: APC loss in transit-amplifying cells
      does not sustain adenoma growth, so the initiating step is restricted to the
      stem cell compartment rather than being a general epithelial effect.
- name: APC-Driven Chromosomal Instability
  biological_scale: CELLULAR
  description: >-
    APC accumulates at the kinetochore during mitosis and is required for efficient
    microtubule attachment. Truncating alleles that remove the APC sequences
    C-terminal to the β-catenin regulatory domain produce chromosome and spindle
    aberrations, so APC loss drives aneuploidy through a route that does not pass
    through β-catenin. This parallel arm is thought to accelerate the accumulation
    of the additional driver lesions required for adenomas to become carcinomas,
    and it is the reason Wnt-directed intervention alone may not capture the whole
    consequence of APC loss.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: chromosome segregation
    modifier: ABNORMAL
    term:
      id: GO:0007059
      label: chromosome segregation
  downstream:
  - target: Colorectal Cancer Progression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Aneuploidy accelerates acquisition of the additional driver mutations that
      convert adenomas to invasive carcinoma.
  evidence:
  - reference: PMID:11283620
    reference_title: Mutations in the APC tumour suppressor gene cause chromosomal instability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation."
    explanation: >-
      Direct genetic evidence that APC loss disrupts chromosome segregation,
      establishing this node as a consequence of APC inactivation rather than of
      Wnt pathway output.
  - reference: PMID:11283620
    reference_title: Mutations in the APC tumour suppressor gene cause chromosomal instability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores."
    explanation: >-
      Names the specific mitotic defect behind the instability, and pairs with the
      report that APC accumulates at the kinetochore during mitosis.
  notes: >-
    Added from the 2026 openscientist hypothesis-search assessment as the
    Wnt-independent arm of APC tumour suppression. Evidence is mouse embryonic stem
    cells and human colorectal cancer cell lines; the relative contribution of this
    arm versus Wnt deregulation to human FAP tumorigenesis has not been separated
    experimentally, which is recorded as a knowledge gap in the discussions section.
- name: Wnt/β-Catenin Pathway Activation
  description: >-
    APC normally functions in the destruction complex (with Axin, GSK3β, CK1)
    to phosphorylate β-catenin, targeting it for ubiquitination and proteasomal
    degradation. Loss of APC allows β-catenin to accumulate, translocate to the
    nucleus, and activate Wnt target genes driving proliferation.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  downstream:
  - target: Uncontrolled Intestinal Epithelial Proliferation
    description: β-catenin activates proliferative and stemness genes
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "germline mutations affect the functional domains of the APC gene that are responsible for interactions of the transcript with β-catenin"
    explanation: >-
      Confirms that pathogenic APC variants disrupt the APC–β-catenin
      interaction domains, the molecular basis for Wnt pathway dysregulation
      downstream of APC loss.
- name: Uncontrolled Intestinal Epithelial Proliferation
  description: >-
    Nuclear β-catenin activates TCF/LEF transcription factors, driving expression
    of Wnt target genes including MYC, CCND1 (cyclin D1), and others that promote
    cell cycle progression. This results in uncontrolled proliferation of
    intestinal crypt cells, forming adenomatous polyps.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Adenoma Formation
    description: Hyperproliferative epithelium forms adenomatous polyps
- name: Adenoma Formation
  conforms_to: "germline_two_hit_tumor_predisposition#Clonal Expansion and Tumor Initiation"
  description: >-
    Sustained Wnt pathway activation drives adenoma development. Adenomas are
    benign neoplasms but represent the first step in the adenoma-carcinoma
    sequence. In FAP, hundreds to thousands of adenomas develop, dramatically
    increasing the probability that one will progress to carcinoma.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: rectum
    term:
      id: UBERON:0001052
      label: rectum
  downstream:
  - target: Colorectal Polyposis
    causal_link_type: DIRECT
    description: Wnt-driven intestinal epithelial adenoma formation produces the hundreds of colonic polyps that define FAP.
    evidence:
    - reference: PMID:28668823
      reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
      explanation: Supports colorectal polyposis as the direct adenoma phenotype in FAP.
  - target: Colorectal Cancer Progression
    description: Accumulated mutations drive adenoma-to-carcinoma progression
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
    explanation: >-
      Hundreds of colonic adenomas with high transformation potential is the
      defining FAP feature that drives near-certain malignant progression.
- name: Colorectal Cancer Progression
  description: >-
    Adenomas acquire additional mutations in KRAS, TP53, SMAD4, and other genes
    through the adenoma-carcinoma sequence. In FAP, the large number of adenomas
    makes it virtually certain that at least one will progress to invasive
    adenocarcinoma without intervention.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
    explanation: >-
      Two-hit inactivation of APC is the critical molecular step in FAP-driven
      colorectal cancer development.
  downstream:
  - target: Colorectal Cancer
    causal_link_type: DIRECT
    description: APC two-hit progression in FAP adenomas drives colorectal cancer development.
    evidence:
    - reference: PMID:28668823
      reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
      explanation: Supports colorectal cancer as a downstream outcome of APC-driven FAP progression.
phenotypes:
- category: Gastrointestinal
  name: Colorectal Polyposis
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Hundreds to thousands of adenomatous polyps carpet the colon and rectum.
    Polyps typically appear in adolescence in classic FAP. The number and
    density of polyps correlates with mutation location in APC.
  phenotype_term:
    preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by the presence of hundreds of colonic polyps, which have a high tendency to undergo malignant transformation."
    explanation: >-
      The defining FAP phenotype is the presence of hundreds of colonic
      adenomatous polyps.
- category: Neoplastic
  name: Colorectal Cancer
  frequency: VERY_FREQUENT
  description: >-
    Without prophylactic surgery, colorectal cancer develops in nearly 100%
    of patients with classic FAP, typically by age 40. The average age of
    cancer diagnosis is 39 years without surveillance/intervention. The age at
    which risk rises is genotype dependent rather than uniform: in a genetically
    confirmed Japanese registry cohort the risk of stage II-IV colorectal cancer
    rose sharply at about age 34 in patients whose variant lay outside the
    attenuated-FAP-associated regions and only at about age 49 in those whose
    variant lay inside them.
  phenotype_term:
    preferred_term: Colon cancer
    term:
      id: HP:0003003
      label: Colon cancer
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids."
    explanation: >-
      Colorectal cancer is the principal malignant outcome of FAP,
      driven by two-hit APC inactivation.
  - reference: PMID:37853284
    reference_title: >-
      Usefulness of genotyping APC gene for individualizing management of patients
      with familial adenomatous polyposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk of stage II-IV CRC was estimated to increase markedly at the age of 49\xA0years in the Genotype-1 patients and 34\xA0years in the Genotype-2 patients, respectively."
    explanation: >-
      Source for the genotype-dependent timing sentence added above. Genotype-1 is
      defined in this study as variants in attenuated-FAP-associated regions and
      Genotype-2 as all others, so the 34-versus-49 split is a genotype effect on
      when to intervene, not on whether cancer eventually occurs. Bounds worth
      keeping in view: 171 patients in a retrospective Japanese multicentre
      registry, and the inflection is specific to stage II-IV disease.
- category: Gastrointestinal
  name: Duodenal Adenomas
  frequency: VERY_FREQUENT
  description: >-
    Duodenal adenomas, especially periampullary, develop in nearly all FAP
    patients. They carry risk of progression to duodenal/ampullary
    adenocarcinoma, which is a leading cause of death in post-colectomy FAP
    patients.
  phenotype_term:
    preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: DOI:10.1055/a-2011-1933
    reference_title: "Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all patients with FAP will also develop adenomas in the duodenum, but only 4 % to 10 % duodenal cancer"
    explanation: >-
      Confirms duodenal adenomas develop in nearly all FAP patients, though
      only a minority progress to duodenal cancer.
  - reference: DOI:10.1055/a-2011-1933
    reference_title: "Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duodenal cancer generally has a poor prognosis and is one of\nthe most common FAP-related causes of death"
    explanation: >-
      Supports duodenal/ampullary cancer as a leading cause of death in FAP
      patients.
- category: Musculoskeletal
  name: Desmoid Tumors
  frequency: FREQUENT
  description: >-
    Desmoid tumors (aggressive fibromatoses) occur in 10-15% of FAP patients,
    often in the mesentery or abdominal wall. They can cause significant
    morbidity through local invasion and compression. More common with 3' APC
    mutations and after abdominal surgery.
  phenotype_term:
    preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    snippet: >-
      Among associated lesions in FAP, desmoid tumors represent a common possible
      life-threatening condition that requires special attention. They are rare
      tumors occurring with a particularly high incidence in FAP, especially after
      surgery.
    explanation: >-
      Review confirms desmoid tumors are a serious complication of FAP with
      particularly high incidence after abdominal surgery.
- category: Musculoskeletal
  name: Osteomas
  description: >-
    Benign bony growths, particularly of the mandible and skull. Characteristic
    of Gardner syndrome phenotype. May be detected radiographically before
    polyposis becomes apparent.
  notes: >-
    Frequency band omitted: the cited GeneReviews source describes extracolonic
    manifestations as "variably present" without a quantitative frequency, which
    supports the disease-phenotype association but not a FrequencyEnum band
    (see docs/frequency-evidence-guidelines.md).
  phenotype_term:
    preferred_term: Osteoma
    term:
      id: HP:0100246
      label: Osteoma
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extracolonic manifestations are variably\npresent and include polyps of the stomach and duodenum, osteomas, dental \nabnormalities"
    explanation: >-
      GeneReviews lists osteomas among the extracolonic manifestations of FAP.
- category: Ophthalmologic
  name: Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
  description: >-
    Pigmented lesions of the retinal pigment epithelium present from birth.
    Multiple bilateral CHRPE lesions are highly specific for FAP and can be
    detected before polyp development, aiding early diagnosis.
  notes: >-
    Frequency band omitted: the cited GeneReviews source describes extracolonic
    manifestations as "variably present" without a quantitative frequency, which
    supports the disease-phenotype association but not a FrequencyEnum band
    (see docs/frequency-evidence-guidelines.md).
  phenotype_term:
    preferred_term: Abnormality of retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE)"
    explanation: >-
      GeneReviews lists CHRPE among the extracolonic manifestations of FAP.
biochemical:
- name: APC Genetic Testing
  notes: >-
    Molecular testing identifies germline APC mutations in 70-90% of classic FAP
    families. Mutations include truncating variants, large deletions, and deep
    intronic variants. Genotype-phenotype correlations exist: mutations in the
    MCR (codons 1250-1464) cause severe polyposis; 5'/3' mutations cause AFAP.
genetic:
- name: APC
  gene_term:
    preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    APC (5q22.2) encodes adenomatous polyposis coli, a key component of the
    β-catenin destruction complex. Most germline mutations are truncating
    (nonsense, frameshift) resulting in loss of function. De novo mutations
    account for 20-30% of cases. Mutation location correlates with phenotype:
    MCR mutations (codons 1250-1464) cause classic severe FAP; 5' mutations
    (before codon 157) and 3' mutations (after codon 1595) cause attenuated FAP.
    Postzygotic APC mosaicism is a further route to the same phenotype and
    accounts for a substantial share of polyposis that germline testing leaves
    unexplained; detection depends on the sequencing method and on the tissue
    assayed, with multiple colorectal adenomas more informative than leukocyte
    DNA.
  evidence:
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    snippet: >-
      Several lines of evidence show that germline mutations affect the functional
      domains of the APC gene that are responsible for interactions of the transcript
      with β-catenin, whereas somatic second mutations involve the downstream region
      of the gene.
    explanation: >-
      Supports APC domain involvement and second-hit pattern, but does not fully
      cover all detailed genotype-phenotype and de novo rate claims in this entry.
  - reference: PMID:18433509
    reference_title: >-
      Clinical characterization and the mutation spectrum in Swedish adenomatous
      polyposis families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017)."
    explanation: >-
      Substantiates the mutation-cluster-region genotype-phenotype claim asserted in
      the notes above, in 96 unrelated families from the Swedish Polyposis Registry.
      The same series reports dense polyposis (>1000 adenomas) in 75% of severe
      versus 30% of non-severe genotypes.
  - reference: PMID:40237877
    reference_title: >-
      A review of APC somatic mosaicism and specific APC variants - I1307K and
      promotor variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APC somatic (postzygotic) mosaicism can be identified in up to 50% of unexplained adenomatous polyposis cases."
    explanation: >-
      Source for the mosaicism sentence added to the notes above. Mosaicism extends
      APC's causal role to polyposis that germline testing scores as mutation
      negative, which changes both the testing strategy and the risk assessment
      offered to relatives.
  - reference: PMID:40237877
    reference_title: >-
      A review of APC somatic mosaicism and specific APC variants - I1307K and
      promotor variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ability to identify APC postzygotic mosaicism depends on the the detection method (today usually next-generation sequencing) and also the tissue being analysed (investigation of multiple colorectal adenomas is more sensitive than leukocyte DNA)."
    explanation: >-
      Supports the tissue-sensitivity qualification in the notes: a leukocyte-only
      panel can miss mosaic APC that adenoma sequencing detects.
  - reference: CGGV:assertion_cdf062b6-6abf-49f6-a2dc-43b0e535f1b6-2022-06-20T170000.000Z
    reference_title: APC / classic or attenuated familial adenomatous polyposis (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APC | HGNC:583 | classic or attenuated familial adenomatous polyposis | MONDO:0021057 | AD | Definitive | SOP9 | Hereditary Cancer Gene Curation Expert Panel"
    explanation: >-
      ClinGen's Hereditary Cancer Gene Curation Expert Panel classifies the
      APC gene-disease relationship with classic or attenuated FAP as Definitive
      under autosomal dominant inheritance. This is the gene-disease validity
      record; the variant-classification panel cited below is a separate product.
  - reference: PMID:37800450
    reference_title: >-
      Gene-specific ACMG/AMP classification criteria for germline APC variants:
      Recommendations from the ClinGen InSiGHT Hereditary Colorectal
      Cancer/Polyposis Variant Curation Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25)."
    explanation: >-
      Records the APC-specific variant-classification framework that governs how a
      germline APC variant found in a proband is called pathogenic. It bears on
      variant interpretation, not on gene-disease validity, which is why it is
      cited separately from the ClinGen gene-disease record above.
treatments:
- name: Prophylactic Colectomy
  description: >-
    Surgical removal of the colon is the primary management to prevent colorectal
    cancer. Options include total proctocolectomy with ileal pouch-anal anastomosis
    (IPAA) or subtotal colectomy with ileorectal anastomosis (IRA). Timing is
    typically in late teens/early twenties or when polyp burden becomes
    unmanageable endoscopically.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colectomy to reduce the risk for CRC in individuals with \nclassic FAP"
    explanation: >-
      GeneReviews recommends colectomy as the standard measure to prevent
      colorectal cancer in classic FAP.
- name: Endoscopic Surveillance
  description: >-
    Colonoscopy every one to two years beginning at age 10-15 years in at-risk
    individuals with classic FAP (late adolescence in attenuated FAP) to detect
    polyp development. Esophagogastroduodenoscopy with visualization of the
    ampulla of Vater by age 20-25 years or prior to colon surgery, with duodenal
    adenoma burden graded by Spigelman stage. Surveillance of rectal stump or
    pouch after colectomy.
  treatment_term:
    preferred_term: colonoscopy
    term:
      id: NCIT:C16450
      label: Colonoscopy
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colorectal \nscreening by colonoscopy every one to two years beginning at age ten to 15 years \nfor classic FAP and in late adolescence for attenuated FAP"
    explanation: >-
      GeneReviews specifies the colonoscopy surveillance interval and starting
      age for classic and attenuated FAP.
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "esophagogastroduodenoscopy with visualization of the ampulla of Vater by age 20 \nto 25 years or prior to colon surgery, with consideration of complete small \nbowel visualization in the setting of advanced Spigelman stage"
    explanation: >-
      GeneReviews specifies the upper-endoscopy surveillance recommendation,
      including ampullary visualization and the role of Spigelman stage.
- name: Genetic Counseling
  description: >-
    Genetic counseling and testing for at-risk family members. Children of
    affected parents have 50% risk. Predictive testing allows targeted
    surveillance in mutation carriers and reassurance for non-carriers.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular genetic testing for early identification of at-risk family members \nimproves diagnostic certainty and reduces the need for costly screening \nprocedures in those at-risk family members who have not inherited the pathogenic \nvariant"
    explanation: >-
      GeneReviews supports genetic testing of at-risk relatives to guide
      surveillance and reassure non-carriers.
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Offspring of an \naffected individual are at a 50% risk of inheriting the pathogenic variant in \nAPC."
    explanation: >-
      GeneReviews states the 50% offspring recurrence risk that this counseling
      recommendation is built on.
- name: Chemoprevention
  description: >-
    Sulindac and celecoxib (COX-2 inhibitors) have demonstrated ability to
    reduce polyp number and size but do not eliminate cancer risk. Used as
    adjunct to surveillance, not as alternative to surgery.
  treatment_term:
    preferred_term: chemoprevention
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sulindac
      term:
        id: CHEBI:9352
        label: sulindac
    - preferred_term: celecoxib
      term:
        id: CHEBI:41423
        label: celecoxib
  evidence:
  - reference: PMID:20301519
    reference_title: "APC-Associated Polyposis Conditions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several studies have shown that NSAIDs and \nerlotinib have caused regression of adenomas and decreased the polyp burden in \nindividuals with FAP, though there are currently no FDA-approved chemopreventive \nagents for FAP"
    explanation: >-
      GeneReviews notes NSAID-class chemoprevention reduces polyp burden but
      is not FDA-approved as a cancer-risk-modifying therapy in FAP.
discussions:
- discussion_id: apc_beta_catenin_nuclear_localization_discordance
  prompt: >-
    Does APC inactivation invariably produce nuclear β-catenin accumulation in FAP
    adenomas, or can APC loss drive tumorigenesis with transcriptional Wnt output
    decoupled from β-catenin nuclear localization?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Wnt/β-Catenin Pathway Activation
  rationale: >-
    The edge from APC loss to nuclear β-catenin is the load-bearing step of the
    canonical model, and it has been reported not to hold. Bala et al. found no
    correlation between APC mutation and β-catenin nuclear localization on serial
    sections of the same tumour regions, and could not explain the discordance by
    KRAS status; the result reproduced in colorectal cancer cell lines carrying
    various APC mutations. The scope limit matters: those samples are early-onset
    sporadic rectal cancers, not FAP adenomas, so the gap is whether the same
    decoupling occurs in the germline-APC setting this entry models. Spatial
    heterogeneity of Wnt output within a tumour could explain part of the finding
    as an immunohistochemistry sampling artefact, but has not been shown to explain
    all of it. If the decoupling is real in FAP, then nuclear β-catenin is an
    unreliable pharmacodynamic readout for Wnt-directed intervention, and part of
    APC's tumour-initiating function runs through some other output.
  proposed_experiments:
  - experiment_id: exp_fap_acute_apc_deletion_beta_catenin_dynamics
    name: Single-cell β-catenin dynamics after acute APC deletion in FAP organoids
    description: >-
      Induce acute biallelic APC deletion with inducible Cre in patient-derived
      intestinal organoids from FAP carriers and from non-carrier controls, then
      track β-catenin subcellular localization, TCF/LEF transcriptional output, and
      cell fate at single-cell resolution over roughly two weeks. Read nuclear
      β-catenin by immunocytochemistry against Wnt target gene expression by
      single-cell RNA sequencing in the same cells, and score a chromosomal
      instability marker in parallel so a discordant cell can be checked for the
      alternative APC output.
    would_support:
    - pathophysiology#Wnt/β-Catenin Pathway Activation
    supporting_outcome:
    - >-
        APC deletion is followed in essentially every transformed cell by nuclear
        β-catenin accumulation together with matching TCF/LEF target induction,
        making the reported discordance an artefact of fixed-tissue sampling or of
        the sporadic rectal cancer context.
    refuting_outcome:
    - >-
        A reproducible subpopulation shows Wnt target induction without nuclear
        β-catenin, or transformation without either, identifying conditions under
        which the canonical APC to nuclear β-catenin link does not hold in cells of
        FAP origin.
  evidence:
  - reference: PMID:36586069
    reference_title: >-
      To β or Not to β: Lack of Correlation Between APC Mutation and β-Catenin
      Nuclear Localization in Colorectal Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of correlation was validated in CRC cell lines harboring various APC mutations."
    explanation: >-
      Establishes that the discordance survives in a controlled cell-line setting
      rather than being a property of one tissue series, which is what makes it a
      knowledge gap rather than a sampling complaint.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report, whose Gap 1 flags
    this as the highest-impact challenge to the canonical model. The assessment
    sidecar qualifies the claim on scope (sporadic early-onset rectal cancer, not
    FAP).
- discussion_id: wnt_versus_chromosomal_instability_contribution
  prompt: >-
    How much of APC's tumour-suppressive function in FAP is carried by Wnt
    regulation and how much by its role in chromosome segregation, and does that
    balance differ between adenoma initiation and progression to carcinoma?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#APC-Driven Chromosomal Instability
  - pathophysiology#Wnt/β-Catenin Pathway Activation
  rationale: >-
    Both arms are established individually. APC loss deregulates β-catenin, and
    separately produces chromosome and spindle aberrations through sequences lying
    C-terminal to the β-catenin regulatory domain. What has not been done is a
    separation-of-function experiment that quantifies their relative contributions,
    so the entry carries two parallel edges out of APC loss without being able to
    weight them. This is not an academic point: if instability contributes
    materially to initiation rather than only to progression, an intervention that
    normalises Wnt output would leave part of the mechanism running.
  proposed_experiments:
  - experiment_id: exp_apc_separation_of_function_alleles
    name: Separation-of-function APC alleles in intestinal organoids
    description: >-
      Engineer APC variants that retain β-catenin regulation but lose the
      kinetochore-associated function, and the converse, then express each in
      Apc-null intestinal organoids. Score adenoma-like outgrowth, karyotype
      stability, and progression kinetics as separate outcomes rather than as a
      single transformation endpoint.
    would_support:
    - pathophysiology#APC-Driven Chromosomal Instability
    supporting_outcome:
    - >-
        A Wnt-competent but instability-deficient APC allele fails to suppress
        transformation fully, showing that chromosome segregation control is a
        non-redundant part of APC tumour suppression.
    refuting_outcome:
    - >-
        A Wnt-competent APC allele suppresses outgrowth as completely as wild-type
        APC regardless of its effect on segregation, placing the instability arm
        downstream of, or incidental to, Wnt deregulation in this setting.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report Gap 2. The
    supporting sources for the instability arm itself are cited on the
    pathophysiology node; nothing is cited here because the gap is precisely that
    the comparative experiment has not been reported.
- discussion_id: human_fap_polyp_burden_modifier_genes
  prompt: >-
    Which human genetic modifiers account for the variation in polyp burden and age
    at diagnosis seen among FAP patients carrying the same APC variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Colorectal Polyposis
  rationale: >-
    Mouse work established that background genotype alone changes adenoma
    multiplicity several fold at a fixed Apc mutation, so modifiers are real in
    principle, and intrafamilial variability in FAP families sharing one APC
    variant says they are likely real in patients. The human loci are unidentified.
    The mouse candidate that came closest, Pla2g2a at the Mom1 locus, did not
    transfer: human studies did not confirm PLA2G2A as a major modifier because the
    relevant functional polymorphism does not exist in humans. Until human
    modifiers are known, APC genotype is the only stratifier available for deciding
    surveillance intensity and the timing of prophylactic surgery, and it does not
    explain the observed spread.
  proposed_experiments:
  - experiment_id: exp_fap_modifier_gwas
    name: Modifier GWAS across FAP registries stratified by APC genotype
    description: >-
      Assemble more than 500 genetically confirmed FAP patients across national
      polyposis registries, use cumulative polyp burden and age at first adenoma as
      quantitative phenotypes, and adjust for APC variant position so that the
      known genotype effect does not absorb the modifier signal.
    would_support:
    - phenotypes#Colorectal Polyposis
    supporting_outcome:
    - >-
        Replicating modifier loci reach significance for polyp burden independently
        of APC variant position, giving a stratifier that APC genotype alone does not
        provide.
    refuting_outcome:
    - >-
        No locus reaches significance at adequate power, indicating the residual
        variation is environmental, stochastic, or driven by rare variants that a
        common-variant scan cannot see.
  evidence:
  - reference: PMID:15710876
    reference_title: >-
      Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unfortunately, studies in humans did not confirmPLA2G2Aas a major modifier of colorectal cancer risk in humans because functional polymorphic variation did not exist"
    explanation: >-
      Records the failure of the leading mouse modifier candidate to transfer to
      humans, which is what leaves the human modifier question open. Note the
      quoted sentence comes from the paper's own account of prior work; the study
      itself attributes its 3-to-5-fold multiplicity difference to a locus near Apc
      or to structural variation on chromosome 18, not to Mom1/Pla2g2a.
  notes: >-
    Raised from the 2026 openscientist hypothesis-search report Gap 4. The
    assessment sidecar qualifies that report's attribution of the mouse effect to
    Mom1/Pla2g2a. Missing spaces in the quoted snippet are an artefact of the
    cached full text and are reproduced verbatim.
disease_term:
  preferred_term: familial adenomatous polyposis 1
  term:
    id: MONDO:0021056
    label: familial adenomatous polyposis 1
references:
- reference: PMID:20301519
  title: "APC-Associated Polyposis Conditions."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s00384-024-04776-8
  title: 'Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis'
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity.
    supporting_text: Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity.
    evidence:
    - reference: DOI:10.1007/s00384-024-04776-8
      reference_title: 'Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.1007/s10689-025-00460-0
  title: Genetics, genomics and clinical features of adenomatous polyposis
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Genetics, genomics and clinical features of adenomatous polyposis
    supporting_text: Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies.
    evidence:
    - reference: DOI:10.1007/s10689-025-00460-0
      reference_title: Genetics, genomics and clinical features of adenomatous polyposis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.1007/s10689-025-00462-y
  title: 'Guidelines for Familial Adenomatous Polyposis (FAP): challenges in defining clinical management for a rare disease'
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally.
    supporting_text: Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally.
    evidence:
    - reference: DOI:10.1007/s10689-025-00462-y
      reference_title: 'Guidelines for Familial Adenomatous Polyposis (FAP): challenges in defining clinical management for a rare disease'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.1007/s44197-023-00171-8
  title: Surveillance Compliance and Quality of Life Assessment Among Surgical Patients with Familial Adenomatous Polyposis Syndrome
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer.
    supporting_text: Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer.
    evidence:
    - reference: DOI:10.1007/s44197-023-00171-8
      reference_title: Surveillance Compliance and Quality of Life Assessment Among Surgical Patients with Familial Adenomatous Polyposis Syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.1038/s41431-024-01585-z
  title: 'Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study'
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP).
    supporting_text: In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP).
    evidence:
    - reference: DOI:10.1038/s41431-024-01585-z
      reference_title: 'Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP).
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.1055/a-2011-1933
  title: 'Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy'
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer.
    supporting_text: Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer.
    evidence:
    - reference: DOI:10.1055/a-2011-1933
      reference_title: 'Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
- reference: DOI:10.2147/tacg.s372241
  title: Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis
    supporting_text: Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis
- reference: DOI:10.3390/ijms24065687
  title: Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis
  found_in:
  - Familial_Adenomatous_Polyposis-deep-research-falcon.md
  findings:
  - statement: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations.
    supporting_text: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations.
    evidence:
    - reference: DOI:10.3390/ijms24065687
      reference_title: Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations.
      explanation: Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
datasets:
- accession: ega:EGAS00001003598
  title: Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis
  description: Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Familial Adenomatous Polyposis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: dbgap:phs000904
  title: APC Promoter Deletion in Classic Familial Adenomatous Polyposis
  description:  The ~80% of individuals with classic familial adenomatous polyposis (FAP) have detectable mutations in the coding sequence of the adenomatous polyposis coli (APC) gene. To investigate the 20% of families without detectable causative mutations, we used exome sequencing and second-generation sequencing of the APC locus including non-coding regions. We identified a novel ~11kb deletion 44kb upstream of APC that was present only in affected individuals of three kindreds.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Familial Adenomatous Polyposis"). Retrieved 2026-08-02.
📚

References & Deep Research

References

9
PMID:20301519
APC-Associated Polyposis Conditions.
No top-level findings curated for this source.
DOI:10.1007/s00384-024-04776-8
Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis
1 finding
Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity.
"Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity."
Show evidence (1 reference)
DOI:10.1007/s00384-024-04776-8 SUPPORT Human Clinical
"Colorectal cancer (CRC) and polypoid syndromes are significant public health concerns, with somatic mosaicism playing a crucial role in their genetic diversity."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.1007/s10689-025-00460-0
Genetics, genomics and clinical features of adenomatous polyposis
1 finding
Genetics, genomics and clinical features of adenomatous polyposis
"Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies."
Show evidence (1 reference)
DOI:10.1007/s10689-025-00460-0 SUPPORT Other
"Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.1007/s10689-025-00462-y
Guidelines for Familial Adenomatous Polyposis (FAP): challenges in defining clinical management for a rare disease
1 finding
Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally.
"Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally."
Show evidence (1 reference)
DOI:10.1007/s10689-025-00462-y SUPPORT Other
"Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.1007/s44197-023-00171-8
Surveillance Compliance and Quality of Life Assessment Among Surgical Patients with Familial Adenomatous Polyposis Syndrome
1 finding
Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer.
"Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer."
Show evidence (1 reference)
DOI:10.1007/s44197-023-00171-8 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) syndrome has a near-100% lifetime risk of colorectal cancer."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.1038/s41431-024-01585-z
Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study
1 finding
In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP).
"In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP)."
Show evidence (1 reference)
DOI:10.1038/s41431-024-01585-z SUPPORT Human Clinical
"In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP)."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.1055/a-2011-1933
Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy
1 finding
Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer.
"Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer."
Show evidence (1 reference)
DOI:10.1055/a-2011-1933 SUPPORT Other
"Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.
DOI:10.2147/tacg.s372241
Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis
1 finding
Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis
"Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis"
DOI:10.3390/ijms24065687
Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis
1 finding
Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations.
"Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations."
Show evidence (1 reference)
DOI:10.3390/ijms24065687 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations."
Deep research cited this publication as relevant literature for Familial Adenomatous Polyposis.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Cancer-predisposition evidence review: Familial_Adenomatous_Polyposis (gaps flagged) · 2026-07-11T18:45:53Z · View source

Manual cancer-predisposition evidence-integrity review: every cited evidence item's snippet was checked as an exact quote of the cached abstract/record and judged for whether it genuinely supports the claim (polarity, evidence_source, named-entity confusion, frequency-band support). Part of a 30-entry hereditary-cancer-predisposition sweep. Outcome: all snippets verified exact and NEC-clean, but several mechanistic/phenotype claims and all four treatments are uncited (duodenal-adenoma 80-90%, osteomas, CHRPE); a tangential DR bibliography lead (DOI:10.6004/jnccn.2024.0061) is about endometrial/Lynch cancer, not FAP. Flagged for follow-up curation in the review tracking issue.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-05-08T15:26:15.455085

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Familial Adenomatous Polyposis
  • MONDO ID: (if available)
  • Category:

Research Objectives

Please provide a comprehensive research report on Familial Adenomatous Polyposis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Familial Adenomatous Polyposis (FAP): Disease Characteristics Research Report (2026-05-08)

Executive summary

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal adenomatous polyposis syndrome caused primarily by germline loss-of-function pathogenic variants in APC, leading to the development of hundreds-to-thousands of colorectal adenomas beginning in late childhood/adolescence and (if untreated) an approximately inevitable progression to colorectal cancer (CRC). (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)

Key 2023–2024 themes in the literature retrieved here include: (i) personalized endoscopic surveillance protocols proposed by the European FAP Consortium to standardize lower- and upper-GI surveillance and endoscopic interventions, with prospective evaluation planned; (ii) expanding focus on APC post-zygotic (somatic) mosaicism and the need for mosaicism-aware testing strategies; and (iii) persistent lack of an ideal chemopreventive drug despite many trials, with new pathway targets (eg, mTOR) and ongoing/early-phase strategies. (kyriakidis2023updatedperspectiveson pages 10-12, aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)

1. Disease information

1.1 Definition and overview

FAP is a hereditary cancer syndrome characterized by extensive colorectal adenomatous polyposis (classically hundreds-to-thousands of adenomas) starting in adolescence; without risk-reducing surgery, CRC is near-certain by mid-adulthood (often by ~50 years). (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)

Attenuated FAP (AFAP/aFAP) is a milder clinical form typically presenting with fewer than 100 colorectal adenomas and later onset (often >40 years), and is also associated with specific regions of APC pathogenic variants. (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 2-4)

1.2 Key identifiers and synonyms

A structured set of identifiers/synonyms is summarized in the artifact below; note that MONDO/Orphanet/ICD/MeSH identifiers were not directly retrievable from the tool-accessed evidence in this run, so those are flagged as “not retrieved.”

Identifier system Identifier/code Name used in system Notes
OMIM #175100 Familial adenomatous polyposis OMIM number explicitly reported in a 2023 FAP case report; FAP described as APC-related hereditary colorectal polyposis (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Orphanet not retrieved in tool evidence not retrieved in tool evidence Not directly retrieved from gathered evidence
ICD-10 not retrieved in tool evidence not retrieved in tool evidence Not directly retrieved from gathered evidence
ICD-11 not retrieved in tool evidence not retrieved in tool evidence Not directly retrieved from gathered evidence
MeSH not retrieved in tool evidence not retrieved in tool evidence Not directly retrieved from gathered evidence
MONDO not retrieved in tool evidence not retrieved in tool evidence Not directly retrieved from gathered evidence
Synonym / related entity Relationship to FAP Notes
Classic FAP Core disease form Defined by hundreds to thousands of colorectal adenomas; commonly operationalized as ≥100 adenomas in comparative guideline/review evidence (zare2025guidelinesforfamilial pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2, zare2025guidelinesforfamilial pages 4-4)
Attenuated FAP (AFAP, aFAP) Recognized milder allelic/clinical form Later onset, usually <100 adenomas, milder phenotype; APC-associated (kyriakidis2023updatedperspectiveson pages 2-4, kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 2-4)
APC-associated polyposis conditions Broader umbrella related to FAP Supported indirectly by evidence discussing APC-driven polyposis spectrum and APC-specific variants/promoter disease; exact formal label not retrieved in tool evidence (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Gardner syndrome Historical/phenotypic variant related to FAP Exact definition not retrieved in tool evidence; extracolonic features such as osteomas, dental abnormalities, skin lesions, and CHRPE are reported within FAP spectrum, consistent with historical Gardner terminology (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Turcot syndrome Historical overlap term Exact definition not retrieved in tool evidence; medulloblastoma is listed among extracolonic malignant risks in FAP, consistent with historical overlap usage (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

Table: This artifact summarizes disease identifiers explicitly supported by the gathered evidence and distinguishes between directly retrieved identifiers versus those not retrieved. The second table clarifies commonly used synonyms and historical related entities relevant to interpreting FAP literature and knowledge-base mapping.

Evidence source type note: The overview/identifier information above is derived from aggregated review/guideline-type resources plus some patient-level case series/case reports. (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2, alhassan2024surveillancecomplianceand pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): Germline pathogenic variants in APC (tumor suppressor) are the main cause of autosomal dominant FAP, with tumor initiation typically requiring a somatic “second hit” in the remaining functional allele, activating Wnt/β-catenin signaling. (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 2-4)

Direct abstract quote (mechanistic framing): A 2023 mechanistic review describes FAP as being “based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern.” (ditonno2023molecularpathwaysof pages 1-2)

2.2 Risk factors

Genetic risk factors

  • APC pathogenic variant location and phenotype: Classical FAP tends to be associated with truncating variants; mutation site influences phenotype severity, including extracolonic risks (eg, desmoids). (kyriakidis2023updatedperspectiveson pages 2-4, ditonno2023molecularpathwaysof pages 2-4)
  • De novo APC variants: Up to ~30% of APC pathogenic variants may occur de novo, contributing to apparently sporadic presentations. (joo2025geneticsgenomicsand pages 1-2)
  • Somatic (post-zygotic) mosaicism: Post-zygotic APC mosaicism is a clinically important cause of FAP-like phenotypes and complicates detection when only leukocyte DNA is tested. A 2024 systematic review/meta-analysis across CRC/polyposis syndromes (27 studies, 2272 patients) reported an overall mosaicism prevalence of 8.79% (95% CI 5.1–14.70%), and emphasized incorporating mosaicism screening into routine testing for at-risk patients. (moraes2024genomicmosaicismin pages 9-11)
  • Real-world diagnostic yield: In a Danish nationwide re-evaluation of “colorectal polyposis of unknown etiology” (>100 cumulative adenomas), adding WGS and mosaicism screening increased variant detection; pathogenic variants were detected in 16/27 families (60%), and the registry’s proportion of families with known etiology increased to 93%. (karstensen2024reevaluatingthegenotypes pages 1-2)

Environmental/lifestyle and other non-genetic contributors

Non-genetic contributors are increasingly discussed as potential modifiers/alternative mechanisms in multi-adenoma patients, including environmental factors and bacterial genotoxins (eg, colibactin-producing E. coli), but specific quantified gene–environment interactions were not retrieved in the evidence set used here. (joo2025geneticsgenomicsand pages 1-2)

2.3 Protective factors

Specific, validated protective lifestyle factors or protective genetic alleles were not quantified in the retrieved evidence. A 2025 cohort (postoperative patients) suggested procedural choices may reduce desmoid risk (see below). ()

2.4 Gene–environment interactions

The retrieved evidence notes that moderate-risk genes and inherited cancer risk may be influenced by gene–gene or gene–environment interactions in general (NCCN guideline discussion of multigene testing), but it does not provide FAP-specific interaction estimates. (hodan2024geneticfamilialhighriskassessment pages 6-7)

3. Phenotypes

3.1 Core phenotype spectrum (with HPO term suggestions)

A structured phenotype-to-HPO mapping (with only evidence-supported frequencies/risks) is provided below.

Phenotype HPO term (suggest) Evidence-based frequency/risk (with age if stated) Notes (onset/clinical relevance) Key citations (IDs)
Colorectal adenomatous polyposis HP:0002671 Colorectal polyposis Classic FAP: hundreds to thousands of adenomas; attenuated FAP: usually <100 adenomas; polyps typically begin in adolescence / late childhood Core defining phenotype of FAP; attenuated form has later onset and milder burden (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2, ditonno2023molecularpathwaysof pages 2-4)
Colorectal cancer HP:0003003 Colon carcinoma ~100% lifetime risk if untreated; near-certain CRC by ~50 years without prophylactic surgery; CRC around age 39 in one cited clinical summary Principal malignant consequence and rationale for prophylactic colectomy and early surveillance (kyriakidis2023updatedperspectiveson pages 1-2, alhassan2024surveillancecomplianceand pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Duodenal adenomas / duodenal cancer HP:0100837 Duodenal adenoma; HP:0006749 Duodenal carcinoma Duodenal cancer cumulative risk ~4.5% by age 57 years and ~18% by age 75 years Major extracolonic GI manifestation; upper GI surveillance is standard; European FAP Consortium recommends resection of duodenal adenomas ≥10 mm (kyriakidis2023updatedperspectiveson pages 1-2, aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)
Gastric polyposis / gastric cancer HP:0034390 Gastric polyposis; HP:0006753 Stomach carcinoma Upper GI polyps in ~50% (clinical summary); gastric cancer risk not quantified in retrieved evidence Fundic gland polyposis and gastric adenomas are recognized; recent concern about gastric cancer during surveillance, but numeric lifetime risk not quantified in retrieved evidence (alhassan2024surveillancecomplianceand pages 1-2, aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)
Desmoid tumors HP:0010302 Desmoid tumor 20% reported frequency in FAP; in a 2025 postoperative cohort, 21/202 (10.4%) developed intra-abdominal desmoids after surgery Often mesenteric/intra-abdominal; major cause of morbidity and important in surgical decision-making; risk linked to genotype and operative factors (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Congenital hypertrophy of retinal pigment epithelium (CHRPE) HP:0007759 Congenital hypertrophy of retinal pigment epithelium 60% Common extracolonic feature that may precede intestinal manifestations and aid recognition of APC-associated disease (kyriakidis2023updatedperspectiveson pages 1-2)
Osteomas HP:0002796 Osteoma 20% Classic extracolonic manifestation within the Gardner-spectrum phenotype of FAP (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Dental abnormalities HP:0100339 Abnormality of dentition not quantified in retrieved evidence Includes dental anomalies/supernumerary teeth in APC-associated disease; may precede intestinal polyposis and support early recognition (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
Thyroid cancer HP:0009726 Thyroid carcinoma 1%–2% (papillary thyroid carcinoma in cited review) Recognized extracolonic malignancy; often cited as papillary/cribriform-morular thyroid carcinoma in APC-associated disease (kyriakidis2023updatedperspectiveson pages 1-2, joo2025geneticsgenomicsand pages 1-2)
Hepatoblastoma HP:0002898 Hepatoblastoma 1%–2% Rare pediatric extracolonic malignancy associated with FAP/APC pathogenic variants (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 2-4)
Medulloblastoma HP:0002885 Medulloblastoma 1%–2% Rare CNS malignancy reported in the FAP spectrum; historically overlaps with Turcot terminology (kyriakidis2023updatedperspectiveson pages 1-2, joo2025geneticsgenomicsand pages 1-2)

Table: This table maps major familial adenomatous polyposis phenotypes to suggested HPO terms and summarizes only the frequencies or risks explicitly supported in the retrieved evidence. It is useful for building structured phenotype annotations for a disease knowledge base while preserving citation traceability.

3.2 Upper GI disease and emerging concern for gastric cancer

Upper GI manifestations (duodenal and gastric polyposis/adenomas) are major contributors to morbidity after colorectal risk reduction. A European FAP Consortium paper emphasizes improved upper-GI lesion detection (eg, using NBI/BLI to distinguish gastric adenomas among fundic gland polyps) and provides consensus thresholds for intervention. (aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)

3.3 Quality of life impact (evidence example)

A 2024 single-center cohort of surgically treated FAP patients in Saudi Arabia used SF-36 and reported mean domain scores above 60, while also documenting surveillance adherence gaps (see “Diagnostics/Screening” for implementation implications). (alhassan2024surveillancecomplianceand pages 1-2)

4. Genetic / molecular information

4.1 Causal genes

  • APC (tumor suppressor; central gatekeeper in colorectal tumorigenesis; Wnt signaling regulator). (ditonno2023molecularpathwaysof pages 1-2, ditonno2023molecularpathwaysof pages 2-4)

4.2 Pathogenic variant types and functional consequences

  • Many classical FAP germline variants are nonsense or frameshift truncating variants (reported in a 2023 mechanistic review as common, up to ~80% of cases in that review’s summary framing). (ditonno2023molecularpathwaysof pages 2-4)
  • Variant type/location influences residual APC function and thereby phenotype. (ditonno2023molecularpathwaysof pages 2-4)

4.3 Mosaicism and structural variants (diagnostic relevance)

  • Mosaicism detection can require analysis beyond blood (eg, adenoma tissue). (kyriakidis2023updatedperspectiveson pages 2-4, karstensen2024reevaluatingthegenotypes pages 1-2)
  • WGS can uncover structural variants missed by standard testing; in the Danish cohort, WGS identified additional APC structural variants. (karstensen2024reevaluatingthegenotypes pages 1-2)

4.4 Modifier genes and epigenetics

The retrieved evidence set references phenotypic variability and broader polyposis genetics, but does not provide a definitive, quantified list of FAP modifier genes or epigenetic signatures suitable for a curated knowledge base entry. (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 2-4)

5. Environmental information

Specific environmental exposures causally linked to FAP onset are not applicable in the same way as multifactorial diseases because FAP is primarily monogenic (APC). Environmental and microbial factors are discussed as potential contributors/modifiers of colorectal carcinogenesis and polyposis phenotype variability, but detailed exposure-specific statistics were not retrieved here. (joo2025geneticsgenomicsand pages 1-2, ditonno2023molecularpathwaysof pages 1-2)

6. Mechanism / pathophysiology

6.1 Canonical pathway: APC loss → Wnt/β-catenin activation → adenoma initiation

A key mechanistic chain in FAP is loss of APC function, disabling the β-catenin “destruction complex,” leading to nuclear β-catenin accumulation and transcriptional activation of proliferative programs. (ditonno2023molecularpathwaysof pages 2-4)

Upstream event: germline APC loss-of-function variant (first hit). Downstream events: somatic second hit in APC, adenoma formation, accumulation of additional driver events for carcinoma progression. (ditonno2023molecularpathwaysof pages 2-4)

6.2 “Two-hit” and “just-right” signaling concepts

The 2023 mechanistic review describes a Knudson two-hit model and summarizes evidence that the second hit may be selected to retain partial control of β-catenin signaling (“just-right” model), avoiding lethal overactivation while still promoting growth. (ditonno2023molecularpathwaysof pages 2-4)

6.3 Immune/microbiome/inflammation as modifiers (emerging themes)

Recent reviews highlight possible modifier mechanisms including gut microbiota changes, mucosal barrier immunity, immune microenvironment/inflammation, and hormonal factors (eg, estrogen) as potential chemoprevention targets, though this run did not retrieve specific multi-omics signatures for FAP. (ditonno2023molecularpathwaysof pages 1-2)

6.4 Suggested ontology terms

  • GO biological processes (suggest): Wnt signaling pathway (GO:0016055), regulation of β-catenin-mediated signaling (GO:1904888), regulation of cell proliferation (GO:0042127), epithelial cell proliferation (GO:0050673).
  • CL cell types (suggest): intestinal epithelial cell (CL:0000066), colonic epithelial cell (CL:0000584).

(These are ontology suggestions aligned to mechanisms described in retrieved sources; they are not explicitly enumerated in those sources.) (ditonno2023molecularpathwaysof pages 2-4)

7. Anatomical structures affected

7.1 Organ-level

  • Primary: colon and rectum (adenomatous polyposis; CRC risk). (kyriakidis2023updatedperspectiveson pages 1-2)
  • Major secondary GI sites: duodenum and stomach (adenomas/polyposis; cancer risks). (kyriakidis2023updatedperspectiveson pages 1-2, aelvoet2023personalizedendoscopicsurveillance pages 3-5)
  • Other extracolonic sites: thyroid, retina (CHRPE), mesentery/abdominal soft tissues (desmoids), bone/dentition. (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

7.2 UBERON term suggestions

  • Colon: UBERON:0001155
  • Rectum: UBERON:0001052
  • Duodenum: UBERON:0002114
  • Stomach: UBERON:0000945
  • Thyroid gland: UBERON:0002046

(Anatomy ontology suggestions; not explicitly provided in retrieved sources.)

8. Temporal development

8.1 Onset

Polyps commonly begin in late childhood/adolescence; one clinical summary reports typical polyp onset around age ~16 years. (alhassan2024surveillancecomplianceand pages 1-2)

8.2 Progression

Without prophylactic intervention, CRC can develop early; one clinical summary reports CRC around age ~39 years, and reviews emphasize near-certain CRC by ~50 years without surgery. (alhassan2024surveillancecomplianceand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant inheritance is consistently described, with high/near-complete penetrance for colorectal polyposis/CRC in the absence of intervention. (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)

9.2 Epidemiology (statistics)

  • Prevalence: ~2.29–3.2 per 100,000 (reported in 2023 reviews). (kyriakidis2023updatedperspectiveson pages 1-2, ditonno2023molecularpathwaysof pages 1-2)
  • Birth incidence: ~1 in 8,500 (reported in a 2025 review of adenomatous polyposis genetics). (joo2025geneticsgenomicsand pages 1-2)
  • Contribution to CRC burden: ≤0.5% to ~1% of CRC, depending on the source framing. (joo2025geneticsgenomicsand pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

10. Diagnostics

10.1 Clinical criteria and endoscopy

FAP is clinically diagnosed by extensive adenoma burden (often operationalized as ≥100 colorectal adenomas), and/or by identification of a pathogenic/likely pathogenic APC variant. (kyriakidis2023updatedperspectiveson pages 2-4, zare2025guidelinesforfamilial pages 4-4)

10.2 Genetic testing strategies (current practice themes)

  • When familial APC variant known: single-site testing is recommended (as summarized in a 2023 clinical genetics review referencing NCCN). (kyriakidis2023updatedperspectiveson pages 2-4)
  • When etiology uncertain: multigene panels and, if negative, expanded approaches such as WGS and mosaicism assessment in adenomas can improve yield. (karstensen2024reevaluatingthegenotypes pages 1-2)

10.3 Screening and surveillance: recent real-world protocols and implementation

European FAP Consortium (2023) personalized endoscopic surveillance (real-world implementation)

The European FAP Consortium published consensus-based protocols for: * Lower GI surveillance in patients with ileorectal/ileosigmoid anastomosis (IRA/ISA) and ileal pouch-anal anastomosis (IPAA). (aelvoet2023personalizedendoscopicsurveillance pages 3-5) * Upper GI surveillance (duodenum and stomach) with intervention thresholds and variable surveillance intervals based on endoscopic findings. (aelvoet2023personalizedendoscopicsurveillance pages 5-6)

Intervention thresholds (explicit): endoscopic polypectomy/papillectomy indications include duodenal/ampullary adenomas ≥10 mm (or rapidly progressive ampullary lesion), gastric adenomas ≥5 mm, optical suspicion of HGD, and optional duodenal adenoma ≥5 mm when ≥20 duodenal adenomas are present. (aelvoet2023personalizedendoscopicsurveillance pages 3-5)

Visual evidence (flowcharts): * Lower GI post-surgical surveillance flowcharts (IRA/ISA and IPAA): (aelvoet2023personalizedendoscopicsurveillance media 06b7c6ab) * Upper GI duodenum/stomach surveillance flowchart: (aelvoet2023personalizedendoscopicsurveillance media 86c4e959)

Surveillance adherence (implementation gap)

A 2024 Saudi cohort study of surgically treated FAP patients reported incomplete adherence to recommended surveillance: 78% compliance for pre-operative colonoscopy and EGD, but 38% for initial and 27% for post-operative colonoscopy; thyroid ultrasound compliance was 14%. (alhassan2024surveillancecomplianceand pages 1-2)

NCCN 2024 guideline limitation in this run: Although the NCCN Version 3.2024 document was retrieved and includes extensive multigene testing guidance, this run did not retrieve the FAP-specific surveillance interval/timing tables from that document’s text chunks; therefore, NCCN-specific ages/intervals for FAP surveillance cannot be quoted verbatim from the evidence available here. (hodan2024geneticfamilialhighriskassessment pages 7-8, hodan2024geneticfamilialhighriskassessment pages 8-9, zare2025guidelinesforfamilial pages 4-4)

11. Outcome / prognosis

11.1 CRC risk

Untreated classic FAP is associated with near-certain CRC (often framed as ~100% lifetime CRC risk). (kyriakidis2023updatedperspectiveson pages 1-2, alhassan2024surveillancecomplianceand pages 1-2)

11.2 Desmoid morbidity

Desmoid tumors are a major morbidity driver. In a 2025 postoperative registry cohort (2000–2023; n=202 surgical patients), 21/202 (10.4%) developed intra-abdominal desmoids, and the authors concluded that a minimally invasive rectal-sparing colectomy “appears protective” for desmoid development. ()

12. Treatment

12.1 Surgical and interventional (standard of care)

Risk-reducing colorectal surgery (colectomy or proctocolectomy with reconstruction strategies such as IPAA vs IRA) is the mainstay to prevent CRC. Reviews emphasize prophylactic colectomy as the “gold-standard” risk reduction approach, typically completed by age ~40 in one 2023 review summary, while other sources describe prophylactic colectomy recommended in adolescence/young adulthood depending on phenotype. (kyriakidis2023updatedperspectiveson pages 1-2, alhassan2024surveillancecomplianceand pages 1-2)

12.2 Endoscopic management (emerging practice)

European FAP Consortium protocols formalize endoscopic removal thresholds and surveillance intervals aiming to prevent cancer while reducing surgical interventions, with prospective evaluation planned in a 5-year multi-center study. (aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)

12.3 Pharmacotherapy / chemoprevention (current evidence state)

Multiple chemopreventive agents have been studied (eg, aspirin, celecoxib, sulindac, DFMO-based combinations, erlotinib combinations, metformin, fish oil, turmeric, vitamin C), but a 2023 review concluded no agent yet meets criteria for a durable, safe, clinically meaningful long-term chemoprevention strategy in FAP. (kyriakidis2023updatedperspectiveson pages 10-12)

Pathway-targeting development: The same 2023 review highlights interest in targeting novel pathways including mTOR (eg, small pilot experiences with rapamycin/sirolimus showing reductions in polyp size/grade but with adverse events) and notes ongoing trials/strategies such as TUPELO (REC-4881; MAPK inhibitor) and obeticholic acid. (kyriakidis2023updatedperspectiveson pages 10-12)

12.4 MAXO term suggestions (treatment actions)

  • Prophylactic colectomy / proctocolectomy: MAXO:0001112 (surgical excision; term suggestion)
  • Endoscopic polypectomy: MAXO:0000016 (endoscopic resection; term suggestion)
  • Cancer surveillance (endoscopic): MAXO:0000127 (screening/surveillance; term suggestion)

(Ontology term suggestions; not explicitly enumerated in retrieved sources.)

13. Prevention

13.1 Secondary prevention (dominant strategy)

Early detection and removal of adenomas via endoscopic surveillance and prophylactic surgery is the dominant prevention strategy described across sources. (alhassan2024surveillancecomplianceand pages 1-2, aelvoet2023personalizedendoscopicsurveillance pages 3-5)

13.2 Tertiary prevention

Post-surgical surveillance of retained rectum/pouch and upper GI tract aims to prevent advanced neoplasia and manage adenoma burden. (aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)

14. Other species / natural disease

No naturally occurring FAP-equivalent disease in non-human species was retrieved in this evidence set.

15. Model organisms

Although APC-driven tumorigenesis is commonly studied in genetically engineered mouse models, this run did not retrieve a primary source within the evidence set that explicitly details specific model organism resources (eg, APC^Min/+ phenotypic recapitulation) in a citable way for this report.

Expert interpretation and evidence gaps (authoritative source synthesis)

A 2025 guideline-comparison review argues that most FAP management recommendations remain expert-consensus–driven due to the limited high-quality evidence base typical of rare diseases, and highlights ongoing disagreements (eg, adenoma thresholds and surveillance intensity across jurisdictions). (zare2025guidelinesforfamilial pages 1-2)

The European FAP Consortium’s 2023 surveillance strategy is an example of expert-driven standardization intended to be validated prospectively, reflecting a broader trend toward personalized surveillance and endoscopic intervention rather than relying solely on prophylactic colectomy. (aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance pages 5-6)

Reference URLs and publication dates (from retrieved sources)

  • Kyriakidis F. et al. “Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis.” The Application of Clinical Genetics (Aug 2023). https://doi.org/10.2147/tacg.s372241 (kyriakidis2023updatedperspectiveson pages 1-2)
  • Ditonno I. et al. “Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis.” Int J Mol Sci (Mar 2023). https://doi.org/10.3390/ijms24065687 (ditonno2023molecularpathwaysof pages 1-2)
  • Aelvoet A.S. et al. “Personalized endoscopic surveillance…” Endoscopy International Open (Jan 2023). https://doi.org/10.1055/a-2011-1933 (aelvoet2023personalizedendoscopicsurveillance pages 3-5)
  • Alhassan N. et al. “Surveillance Compliance and Quality of Life…” J Epidemiol Glob Health (Jan 2024). https://doi.org/10.1007/s44197-023-00171-8 (alhassan2024surveillancecomplianceand pages 1-2)
  • Hodan R. et al. “NCCN… Version 3.2024.” JNCCN (Dec 2024). https://doi.org/10.6004/jnccn.2024.0061 (hodan2024geneticfamilialhighriskassessment pages 6-7)
  • Karstensen J.G. et al. “Re-evaluating the genotypes…” Eur J Hum Genet (Published online Mar 12, 2024). https://doi.org/10.1038/s41431-024-01585-z (karstensen2024reevaluatingthegenotypes pages 1-2)
  • de Moraes F.C.A. et al. “Genomic mosaicism in colorectal cancer and polyposis syndromes…” Int J Colorectal Dis (Dec 2024). https://doi.org/10.1007/s00384-024-04776-8 (moraes2024genomicmosaicismin pages 9-11)
  • Zare B., Monahan K.J. “Guidelines for FAP…” Familial Cancer (Apr 2025). https://doi.org/10.1007/s10689-025-00462-y (zare2025guidelinesforfamilial pages 1-2)

References

  1. (joo2025geneticsgenomicsand pages 1-2): Jihoon E. Joo, Julen Viana-Errasti, Daniel D. Buchanan, and Laura Valle. Genetics, genomics and clinical features of adenomatous polyposis. Familial Cancer, Apr 2025. URL: https://doi.org/10.1007/s10689-025-00460-0, doi:10.1007/s10689-025-00460-0. This article has 11 citations and is from a peer-reviewed journal.

  2. (kyriakidis2023updatedperspectiveson pages 1-2): Filippos Kyriakidis, Dionysios Kogias, Theodora Maria Venou, Eleni Karlafti, and Daniel Paramythiotis. Updated perspectives on the diagnosis and management of familial adenomatous polyposis. The Application of Clinical Genetics, 16:139-153, Aug 2023. URL: https://doi.org/10.2147/tacg.s372241, doi:10.2147/tacg.s372241. This article has 22 citations.

  3. (ditonno2023molecularpathwaysof pages 1-2): Ilaria Ditonno, Domenico Novielli, Francesca Celiberto, Salvatore Rizzi, Maria Rendina, Enzo Ierardi, Alfredo Di Leo, and Giuseppe Losurdo. Molecular pathways of carcinogenesis in familial adenomatous polyposis. International Journal of Molecular Sciences, 24:5687, Mar 2023. URL: https://doi.org/10.3390/ijms24065687, doi:10.3390/ijms24065687. This article has 36 citations.

  4. (kyriakidis2023updatedperspectiveson pages 10-12): Filippos Kyriakidis, Dionysios Kogias, Theodora Maria Venou, Eleni Karlafti, and Daniel Paramythiotis. Updated perspectives on the diagnosis and management of familial adenomatous polyposis. The Application of Clinical Genetics, 16:139-153, Aug 2023. URL: https://doi.org/10.2147/tacg.s372241, doi:10.2147/tacg.s372241. This article has 22 citations.

  5. (aelvoet2023personalizedendoscopicsurveillance pages 3-5): Arthur S. Aelvoet, Maria Pellisé, Barbara A.J. Bastiaansen, Monique E. van Leerdam, Rodrigo Jover, Francesc Balaguer, Michal F. Kaminski, John G. Karstensen, Jean-Christophe Saurin, Roel Hompes, Patrick M.M. Bossuyt, Luigi Ricciardiello, Andrew Latchford, and Evelien Dekker. Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the european fap consortium strategy. Endoscopy International Open, 11:E386-E393, Jan 2023. URL: https://doi.org/10.1055/a-2011-1933, doi:10.1055/a-2011-1933. This article has 26 citations and is from a peer-reviewed journal.

  6. (aelvoet2023personalizedendoscopicsurveillance pages 5-6): Arthur S. Aelvoet, Maria Pellisé, Barbara A.J. Bastiaansen, Monique E. van Leerdam, Rodrigo Jover, Francesc Balaguer, Michal F. Kaminski, John G. Karstensen, Jean-Christophe Saurin, Roel Hompes, Patrick M.M. Bossuyt, Luigi Ricciardiello, Andrew Latchford, and Evelien Dekker. Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the european fap consortium strategy. Endoscopy International Open, 11:E386-E393, Jan 2023. URL: https://doi.org/10.1055/a-2011-1933, doi:10.1055/a-2011-1933. This article has 26 citations and is from a peer-reviewed journal.

  7. (ditonno2023molecularpathwaysof pages 2-4): Ilaria Ditonno, Domenico Novielli, Francesca Celiberto, Salvatore Rizzi, Maria Rendina, Enzo Ierardi, Alfredo Di Leo, and Giuseppe Losurdo. Molecular pathways of carcinogenesis in familial adenomatous polyposis. International Journal of Molecular Sciences, 24:5687, Mar 2023. URL: https://doi.org/10.3390/ijms24065687, doi:10.3390/ijms24065687. This article has 36 citations.

  8. (zare2025guidelinesforfamilial pages 1-2): Benjamin Zare and Kevin J. Monahan. Guidelines for familial adenomatous polyposis (fap): challenges in defining clinical management for a rare disease. Familial Cancer, Apr 2025. URL: https://doi.org/10.1007/s10689-025-00462-y, doi:10.1007/s10689-025-00462-y. This article has 12 citations and is from a peer-reviewed journal.

  9. (zare2025guidelinesforfamilial pages 4-4): Benjamin Zare and Kevin J. Monahan. Guidelines for familial adenomatous polyposis (fap): challenges in defining clinical management for a rare disease. Familial Cancer, Apr 2025. URL: https://doi.org/10.1007/s10689-025-00462-y, doi:10.1007/s10689-025-00462-y. This article has 12 citations and is from a peer-reviewed journal.

  10. (kyriakidis2023updatedperspectiveson pages 2-4): Filippos Kyriakidis, Dionysios Kogias, Theodora Maria Venou, Eleni Karlafti, and Daniel Paramythiotis. Updated perspectives on the diagnosis and management of familial adenomatous polyposis. The Application of Clinical Genetics, 16:139-153, Aug 2023. URL: https://doi.org/10.2147/tacg.s372241, doi:10.2147/tacg.s372241. This article has 22 citations.

  11. (alhassan2024surveillancecomplianceand pages 1-2): Noura Alhassan, Hadeel Helmi, Abdullah Alzamil, Afraj Alshammari, Atheer Altamimi, Sulaiman Alshammari, Thamer Bin Traiki, Saleh Albanyan, Khayal AlKhayal, Ahmad Zubaidi, and Omar Al-Obeed. Surveillance compliance and quality of life assessment among surgical patients with familial adenomatous polyposis syndrome. Journal of Epidemiology and Global Health, 14:86-93, Jan 2024. URL: https://doi.org/10.1007/s44197-023-00171-8, doi:10.1007/s44197-023-00171-8. This article has 6 citations and is from a peer-reviewed journal.

  12. (moraes2024genomicmosaicismin pages 9-11): Francisco Cezar Aquino de Moraes, Nayara Rozalem Moretti, Vitor Kendi Tsuchiya Sano, Cristiane Wen Tsing Ngan, and Rommel Mario Rodríguez Burbano. Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis. International Journal of Colorectal Disease, Dec 2024. URL: https://doi.org/10.1007/s00384-024-04776-8, doi:10.1007/s00384-024-04776-8. This article has 1 citations and is from a peer-reviewed journal.

  13. (karstensen2024reevaluatingthegenotypes pages 1-2): John Gásdal Karstensen, Thomas v. Overeem Hansen, Johan Burisch, Malene Djursby, Helle Højen, Majbritt Busk Madsen, Niels Jespersen, and Anne Marie Jelsig. Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study. European Journal of Human Genetics, 32:588-592, Mar 2024. URL: https://doi.org/10.1038/s41431-024-01585-z, doi:10.1038/s41431-024-01585-z. This article has 6 citations and is from a domain leading peer-reviewed journal.

  14. (hodan2024geneticfamilialhighriskassessment pages 6-7): Rachel Hodan, Samir Gupta, Jennifer M. Weiss, Lisen Axell, Carol A. Burke, Lee-May Chen, Daniel C. Chung, Katherine M. Clayback, Seth Felder, Zachariah Foda, Francis M. Giardiello, William Grady, Susan Gustafson, Andrea Hagemann, Michael J. Hall, Heather Hampel, Gregory Idos, Nora Joseph, Nawal Kassem, Bryson Katona, Kaitlyn Kelly, AnnMarie Kieber-Emmons, Sonia Kupfer, Katie Lang, Xavier Llor, Arnold J. Markowitz, Mariana Moreno Prats, Mariana Niell-Swiller, Darryl Outlaw, Sara Pirzadeh-Miller, Niloy Jewel Samadder, David Shibata, Peter P. Stanich, Benjamin J. Swanson, Brittany M. Szymaniak, Jeanna Welborn, Georgia L. Wiesner, Matthew B. Yurgelun, Mary Dwyer, Susan Darlow, and Zeenat Diwan. Genetic/familial high-risk assessment: colorectal, endometrial, and gastric, version 3.2024, nccn clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network : JNCCN, 22 10:695-711, Dec 2024. URL: https://doi.org/10.6004/jnccn.2024.0061, doi:10.6004/jnccn.2024.0061. This article has 97 citations.

  15. (aelvoet2023personalizedendoscopicsurveillance media 06b7c6ab): Arthur S. Aelvoet, Maria Pellisé, Barbara A.J. Bastiaansen, Monique E. van Leerdam, Rodrigo Jover, Francesc Balaguer, Michal F. Kaminski, John G. Karstensen, Jean-Christophe Saurin, Roel Hompes, Patrick M.M. Bossuyt, Luigi Ricciardiello, Andrew Latchford, and Evelien Dekker. Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the european fap consortium strategy. Endoscopy International Open, 11:E386-E393, Jan 2023. URL: https://doi.org/10.1055/a-2011-1933, doi:10.1055/a-2011-1933. This article has 26 citations and is from a peer-reviewed journal.

  16. (aelvoet2023personalizedendoscopicsurveillance media 86c4e959): Arthur S. Aelvoet, Maria Pellisé, Barbara A.J. Bastiaansen, Monique E. van Leerdam, Rodrigo Jover, Francesc Balaguer, Michal F. Kaminski, John G. Karstensen, Jean-Christophe Saurin, Roel Hompes, Patrick M.M. Bossuyt, Luigi Ricciardiello, Andrew Latchford, and Evelien Dekker. Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the european fap consortium strategy. Endoscopy International Open, 11:E386-E393, Jan 2023. URL: https://doi.org/10.1055/a-2011-1933, doi:10.1055/a-2011-1933. This article has 26 citations and is from a peer-reviewed journal.

  17. (hodan2024geneticfamilialhighriskassessment pages 7-8): Rachel Hodan, Samir Gupta, Jennifer M. Weiss, Lisen Axell, Carol A. Burke, Lee-May Chen, Daniel C. Chung, Katherine M. Clayback, Seth Felder, Zachariah Foda, Francis M. Giardiello, William Grady, Susan Gustafson, Andrea Hagemann, Michael J. Hall, Heather Hampel, Gregory Idos, Nora Joseph, Nawal Kassem, Bryson Katona, Kaitlyn Kelly, AnnMarie Kieber-Emmons, Sonia Kupfer, Katie Lang, Xavier Llor, Arnold J. Markowitz, Mariana Moreno Prats, Mariana Niell-Swiller, Darryl Outlaw, Sara Pirzadeh-Miller, Niloy Jewel Samadder, David Shibata, Peter P. Stanich, Benjamin J. Swanson, Brittany M. Szymaniak, Jeanna Welborn, Georgia L. Wiesner, Matthew B. Yurgelun, Mary Dwyer, Susan Darlow, and Zeenat Diwan. Genetic/familial high-risk assessment: colorectal, endometrial, and gastric, version 3.2024, nccn clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network : JNCCN, 22 10:695-711, Dec 2024. URL: https://doi.org/10.6004/jnccn.2024.0061, doi:10.6004/jnccn.2024.0061. This article has 97 citations.

  18. (hodan2024geneticfamilialhighriskassessment pages 8-9): Rachel Hodan, Samir Gupta, Jennifer M. Weiss, Lisen Axell, Carol A. Burke, Lee-May Chen, Daniel C. Chung, Katherine M. Clayback, Seth Felder, Zachariah Foda, Francis M. Giardiello, William Grady, Susan Gustafson, Andrea Hagemann, Michael J. Hall, Heather Hampel, Gregory Idos, Nora Joseph, Nawal Kassem, Bryson Katona, Kaitlyn Kelly, AnnMarie Kieber-Emmons, Sonia Kupfer, Katie Lang, Xavier Llor, Arnold J. Markowitz, Mariana Moreno Prats, Mariana Niell-Swiller, Darryl Outlaw, Sara Pirzadeh-Miller, Niloy Jewel Samadder, David Shibata, Peter P. Stanich, Benjamin J. Swanson, Brittany M. Szymaniak, Jeanna Welborn, Georgia L. Wiesner, Matthew B. Yurgelun, Mary Dwyer, Susan Darlow, and Zeenat Diwan. Genetic/familial high-risk assessment: colorectal, endometrial, and gastric, version 3.2024, nccn clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network : JNCCN, 22 10:695-711, Dec 2024. URL: https://doi.org/10.6004/jnccn.2024.0061, doi:10.6004/jnccn.2024.0061. This article has 97 citations.