Classic Familial Adenomatous Polyposis

Mendelian MONDO:0021055 Pathograph 14 familial adenomatous polyposis

Classic familial adenomatous polyposis (classic FAP) is an autosomal dominant APC-associated polyposis syndrome characterized by extensive colorectal adenoma burden beginning early in life and very high colorectal cancer risk without definitive preventive management. Disease progression follows an APC-initiated adenoma-to-carcinoma trajectory with cooperative WNT, PI3K/mTOR, and genomic instability mechanisms, while upper gastrointestinal and extracolonic disease manifestations remain clinically important across adulthood.

0
Mappings
0
Definitions
1
Inheritance
9
Pathophysiology
0
Histopathology
8
Phenotypes
14
Pathograph
2
Genes
7
Treatments
0
Subtypes
5
Differentials
2
Datasets
4
Trials
0
Models
🏷

Classifications

Harrison's Chapter
cancer hereditary disease
👪

Inheritance

1
Autosomal dominant HP:0000006
Classic FAP is inherited in an autosomal dominant pattern due to pathogenic germline APC variants, with variable disease severity and extracolonic manifestations.
Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (1 reference)
DOI:10.1055/s-0043-1767707 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
The abstract directly supports autosomal dominant APC-mediated inheritance in FAP.
📚

References

24
DOI:10.1038/s43018-024-00831-z
Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis
No top-level findings curated for this source.
DOI:10.1055/s-0043-1767707
Update on Surgical Management of FAP
No top-level findings curated for this source.
DOI:10.1055/s-0043-1770384
Chemoprevention in Inherited Colorectal Cancer Syndromes
No top-level findings curated for this source.
DOI:10.1186/s12967-024-05305-5
Interplay between WNT/PI3K-mTOR axis and the microbiota in APC-driven colorectal carcinogenesis data from a pilot study and possible implications for CRC prevention
No top-level findings curated for this source.
DOI:10.1186/s13023-024-03064-6
Clinical efficacy of metformin in familial adenomatous polyposis and the effect of intestinal flora
No top-level findings curated for this source.
DOI:10.3389/fgene.2024.1391851
Evolutionary history of adenomas to colorectal cancer in FAP families
No top-level findings curated for this source.
DOI:10.3390/ijms25158189
Rare Germline Variants in the Adenomatous Polyposis Coli Gene Associated with Dental and Osseous Anomalies
No top-level findings curated for this source.
DOI:10.3390/cimb46070385
Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes
No top-level findings curated for this source.
PMID:19822006
Familial adenomatous polyposis.
No top-level findings curated for this source.
PMID:16411234
Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts.
No top-level findings curated for this source.
PMID:28668823
Desmoid Tumors in Familial Adenomatous Polyposis.
No top-level findings curated for this source.
PMID:31525261
In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: A systematic review.
No top-level findings curated for this source.
PMID:32905675
Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.
No top-level findings curated for this source.
PMID:33509804
The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis.
No top-level findings curated for this source.
PMID:34775416
Attenuated Familial Adenomatous Polyposis: A Phenotypic Diagnosis but Obsolete Term?
No top-level findings curated for this source.
PMID:35636921
Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis.
No top-level findings curated for this source.
PMID:37119510
Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome.
No top-level findings curated for this source.
PMID:39046601
Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up.
No top-level findings curated for this source.
PMID:39729982
Adenomatous Polyposis Coli Gene Mutations, Risk Factors, and Long-term Outcomes Associated With Desmoid Tumors in Patients With Familial Adenomatous Polyposis After Colectomy in Japan.
No top-level findings curated for this source.
PMID:35321042
Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations.
No top-level findings curated for this source.
clinicaltrials:NCT01483144
Phase III Trial of the Safety and Efficacy of Eflornithine Combined With Sulindac Compared to Eflornithine, Sulindac as Single Agents in Patients With Familial Adenomatous Polyposis
No top-level findings curated for this source.
clinicaltrials:NCT01725490
The Chemopreventive Effect of Metformin in Patients With Familial Adenomatous Polyposis Double Blinded Randomized Controlled Study
No top-level findings curated for this source.
clinicaltrials:NCT02961374
Phase II Trial of Weekly Erlotinib Dosing to Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis
No top-level findings curated for this source.
clinicaltrials:NCT06545526
The Chemopreventive Effect of Celecoxib Monotherapy Versus Combination of Celecoxib and Metformin in Patients With Familial Adenomatous Polyposis a Pilot Randomized Open-label Comparative Study
No top-level findings curated for this source.
⚙

Pathophysiology

9
Germline APC loss-of-function predisposition
Germline pathogenic APC variation establishes a constitutional tumor suppressor deficit that predisposes colonic and rectal epithelium to adenoma development.
intestinal epithelial cell link
colon link rectum link
Show evidence (2 references)
DOI:10.1055/s-0043-1767707 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
Supports APC germline mutation as the initiating pathogenic event in FAP.
PMID:28668823 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is a cancer syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene."
Adds independent support that germline APC mutation is the core inherited initiating event.
APC-initiated WNT pathway activation
APC-initiated tumorigenesis proceeds through activation of canonical WNT signaling as an early mechanistic axis in FAP carcinogenesis.
Wnt signaling pathway link ↑ INCREASED
Show evidence (1 reference)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN."
Supports the APC-to-WNT mechanistic step in progression.
Epithelial hyperproliferation
Precancer transitions in classic FAP involve strong pro-growth molecular remodeling and expanded epithelial proliferative signaling.
intestinal epithelial cell link
cell population proliferation link ↑ INCREASED
Show evidence (1 reference)
DOI:10.1038/s43018-024-00831-z SUPPORT Human Clinical
"Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation."
Supports a broad, early molecular expansion program during precancer progression in FAP.
Adenoma initiation
Early adenomatous lesions arise in colorectal mucosa and provide the substrate for subsequent lesion expansion and malignant progression.
colon link rectum link
Show evidence (1 reference)
PMID:19822006 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life."
Supports adenoma initiation as a discrete early disease event.
PI3K/mTOR co-activation in adenomatous lesions
FAP lesions demonstrate PI3K/mTOR pathway co-activation alongside WNT dysregulation, consistent with pathway cooperation during progression.
TOR signaling link ↑ INCREASED phosphatidylinositol 3-kinase/protein kinase B signal transduction link ↑ INCREASED
Show evidence (1 reference)
DOI:10.1186/s12967-024-05305-5 SUPPORT Human Clinical
"We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs."
Directly supports concurrent WNT and PI3K/mTOR pathway hyperactivation in FAP lesions.
Microbiome-associated pathway modulation
Distinct fecal and lesion-associated microbial signatures correlate with WNT and mTOR pathway readouts in FAP, indicating microbiome-linked modulation of progression biology.
Show evidence (1 reference)
DOI:10.1186/s12967-024-05305-5 SUPPORT Human Clinical
"Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment."
Supports mechanistic coupling between pathway derangement and microbiota signatures in FAP.
Genomic instability accumulation across adenoma grades
Adenoma evolution in classic FAP is marked by increasing chromosomal and DNA repair instability features from tubular adenoma to villous adenoma to carcinoma.
chromosome organization link ↕ DYSREGULATED DNA repair link ↕ DYSREGULATED
Show evidence (2 references)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"Furthermore, a progressive increase in the HRD score (a measure of “genomic scars”) was observed from tubular adenomas to villous adenomas and ultimately to carcinomas."
Supports stepwise accumulation of genomic instability through progression stages.
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability."
Supports CIN and DNA repair disruption as central progression features.
TP53 driver emergence in advanced adenomas
Advanced FAP lesions accumulate TP53 driver events that prime transition to invasive carcinoma.
Show evidence (1 reference)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
Supports TP53 as a key driver event in advanced adenoma evolution.
Adenoma-to-carcinoma transition
Advanced adenomas progress to invasive colorectal carcinoma in the absence of effective preventive intervention.
Show evidence (1 reference)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC)."
Supports adenoma-to-carcinoma transition as a discrete late-stage event.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Classic 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.
●

Phenotypes

8
Digestive 3
Colorectal polyposis OBLIGATE Large intestinal polyposis (HP:0030255)
Show evidence (1 reference)
DOI:10.1038/s43018-024-00831-z SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC)."
Supports hallmark high-burden colorectal polyposis.
Colorectal cancer OBLIGATE Colon cancer (HP:0003003)
Show evidence (1 reference)
PMID:37119510 SUPPORT Human Clinical
"Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
Supports very high CRC risk in classic FAP without definitive prevention.
Duodenal polyposis and neoplasia risk FREQUENT Small intestinal polyposis (HP:0030256)
Show evidence (2 references)
PMID:35636921 SUPPORT Human Clinical
"Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer."
Supports frequent and clinically significant duodenal disease in FAP.
PMID:39046601 SUPPORT Human Clinical
"The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance."
Adds population-level evidence for high duodenal disease burden and surveillance relevance.
Eye 1
Congenital hypertrophy of retinal pigment epithelium VERY_FREQUENT Congenital hypertrophy of retinal pigment epithelium (HP:0007649)
Show evidence (2 references)
PMID:31525261 SUPPORT Human Clinical
"The percentage of FAP patients with CHRPE was found to be 80.00%, whereas the percentage of at-risk patients with CHRPE was 31.12%."
Supports high prevalence of CHRPE in classic FAP and its practical value in screening at-risk cohorts.
PMID:35321042 SUPPORT Human Clinical
"CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP."
Supports diagnostic utility of CHRPE as an early phenotypic marker.
Head and Neck 1
Dental anomalies FREQUENT Abnormality of the dentition (HP:0000164)
Show evidence (1 reference)
DOI:10.3390/ijms25158189 SUPPORT Human Clinical
"Since dental abnormalities often precede intestinal polyposis, dentists have a crucial role in the early identification of patients at risk."
Supports dental anomalies as an early and clinically actionable phenotype in APC-associated disease.
Integument 1
Epidermoid cysts (sebaceous cyst phenotype) FREQUENT Epidermoid cyst (HP:0200040)
Show evidence (1 reference)
PMID:16411234 SUPPORT Human Clinical
"Sebaceous cysts were reported in 51% of the patients, and their APC mutations were evenly distributed in the gene with no particular hotspot."
Supports frequent cystic cutaneous manifestations in APC-associated FAP/Gardner-spectrum disease.
Musculoskeletal 1
Osteomas FREQUENT Osteoma (HP:0100246)
Show evidence (1 reference)
DOI:10.3390/ijms25158189 SUPPORT Human Clinical
"Analyses of our cases and the mutations available in the literature with these manifestations revealed that mutations in the N-terminal region (amino acids 1–~1000) of the protein are more frequently associated with only osseous anomalies, whereas dental manifestations are more prevalent in..."
Supports APC-associated osseous phenotypes including osteoma-predominant extracolonic disease.
Neoplasm 1
Desmoid tumor susceptibility FREQUENT Desmoid tumor (HP:6001034)
Show evidence (2 references)
DOI:10.1055/s-0043-1767707 SUPPORT Human Clinical
"Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed."
Supports desmoid risk as a clinically relevant disease manifestation and management modifier.
PMID:39729982 SUPPORT Human Clinical
"The rate of desmoid tumor development was 30.3% in 66 patients."
Adds quantitative cohort evidence for substantial desmoid susceptibility after colectomy.
🧬

Genetic Associations

2
APC (Germline pathogenic loss-of-function variants)
Autosomal dominant
Show evidence (1 reference)
DOI:10.1055/s-0043-1767707 SUPPORT Human Clinical
"Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
Supports APC as the germline causal driver of disease.
TP53 and cooperating progression drivers (Somatic progression-associated alterations)
Show evidence (1 reference)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
Supports a TP53-dominant transition mechanism in advanced progression.
💊

Treatments

7
Prophylactic colectomy
Action: surgical procedure MAXO:0000004
Definitive colorectal cancer risk reduction in classic FAP is centered on timely colectomy/proctocolectomy, individualized by phenotype and risk context.
Show evidence (2 references)
PMID:37119510 SUPPORT Human Clinical
"Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
Supports colectomy as a core preventive intervention in classic FAP.
DOI:10.1055/s-0043-1767707 SUPPORT Human Clinical
"Generally, proctocolectomy is recommended for FAP patients at the age of 20s."
Supports guideline-aligned timing of prophylactic surgery.
Endoscopic surveillance
Action: colonoscopy MAXO:0001184
Longitudinal endoscopic surveillance remains essential for upper gastrointestinal and post-colectomy lower tract risk management.
Show evidence (2 references)
DOI:10.1055/s-0043-1770384 SUPPORT Human Clinical
"Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy)."
Supports intensive endoscopic screening as a core prevention strategy.
PMID:37119510 SUPPORT Human Clinical
"While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood."
Supports lifelong endoscopic surveillance needs after surgical management.
NSAID and COX-2 inhibitor chemoprevention
Action: pharmacotherapy MAXO:0000058
NSAID-based chemoprevention is used as an adjunctive approach but evidence remains heterogeneous and not sufficient to replace surgery/surveillance.
Mechanism Target:
MODULATES Adenoma initiation — Adjunctive pharmacologic suppression of adenoma-promoting pathways.
Show evidence (1 reference)
DOI:10.1055/s-0043-1770384 SUPPORT Human Clinical
"The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater."
Supports mechanism-level use of adjunct pharmacologic modulation in high-risk hereditary CRC syndromes.
Show evidence (2 references)
DOI:10.1055/s-0043-1770384 SUPPORT Human Clinical
"The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater."
Supports adjunctive chemoprevention strategy in hereditary cancer settings including FAP.
DOI:10.1055/s-0043-1770384 PARTIAL Human Clinical
"However, to date only few compounds have been found to be effective, safe, and tolerable for widespread use."
Supports a cautious interpretation of chemoprevention efficacy and tolerability.
Metformin-based chemoprevention
Action: pharmacotherapy MAXO:0000058
Metformin remains investigational in FAP, with mixed efficacy signals across studies and evidence of pathway-level biologic activity.
Mechanism Target:
INHIBITS PI3K/mTOR co-activation in adenomatous lesions — Metformin is investigated as an mTOR-modulating intervention.
Show evidence (1 reference)
PMID:33509804 SUPPORT Human Clinical
"Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm."
Supports pathway-level inhibition of mTOR signaling by metformin in treated lesions.
Show evidence (2 references)
DOI:10.1186/s13023-024-03064-6 SUPPORT Human Clinical
"One-year metformin therapy for FAP is safe and effective, potentially mediated by modulating the intestinal flora."
Supports favorable efficacy/safety signal in one recent clinical study.
PMID:33509804 REFUTE Human Clinical
"A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo."
Supports conflicting trial evidence showing no significant lesion-regression endpoint benefit.
Erlotinib chemoprevention strategy
Action: pharmacotherapy MAXO:0000058
EGFR-targeted chemoprevention with weekly erlotinib can reduce duodenal burden but adverse events remain common.
Show evidence (2 references)
PMID:35636921 SUPPORT Human Clinical
"Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001)."
Supports clinical efficacy for reducing duodenal polyp burden.
PMID:35636921 PARTIAL Human Clinical
"Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention."
Supports efficacy with important tolerability tradeoffs.
Eflornithine plus sulindac combination
Action: pharmacotherapy MAXO:0000058
Combination DFMO/sulindac has been tested for progression delay, but primary efficacy over monotherapy has not been clearly demonstrated.
Show evidence (1 reference)
PMID:32905675 PARTIAL Human Clinical
"In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone."
Supports limited incremental efficacy of combination therapy in the primary trial analysis.
Genetic counseling and hereditary risk management
Action: genetic counseling MAXO:0000079
Risk counseling and genetic assessment are integral to management of hereditary gastrointestinal cancer syndromes, including APC-associated polyposis families.
Show evidence (1 reference)
DOI:10.3390/cimb46070385 SUPPORT Human Clinical
"The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants."
Supports inclusion of structured genetic counseling as a core management component.
🔬

Biochemical Markers

1
Reduced p-S6 signal after metformin exposure (Reduced in resected colon polyps after treatment)
Show evidence (1 reference)
PMID:33509804 SUPPORT Human Clinical
"Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm."
Supports measurable mTOR-pathway biochemical modulation in treated polyps.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Classic Familial Adenomatous Polyposis:

Attenuated familial adenomatous polyposis Not Yet Curated MONDO:0016362
Overlapping Features AFAP shares APC-related adenomatous polyposis biology with classic FAP but usually presents with lower adenoma burden and later onset.
Distinguishing Features
  • Usually 10 to 100 colorectal adenomas rather than hundreds to thousands.
  • Later age of adenoma appearance and comparatively lower colorectal cancer risk.
Show evidence (2 references)
PMID:19822006 SUPPORT Human Clinical
"A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk."
Supports AFAP as a key differential diagnosis and provides distinguishing clinical criteria.
PMID:34775416 SUPPORT Human Clinical
"Attenuated familial adenomatous polyposis is characterised by low number (≤100) and delayed development of colorectal adenomas."
Provides additional modern cohort-based support for AFAP low-count and delayed-onset distinguishing features.
MUTYH-associated polyposis Not Yet Curated MONDO:0012041
Overlapping Features MAP can phenocopy adenomatous polyposis but differs from classic FAP by recessive inheritance and MUTYH etiology.
Distinguishing Features
  • Autosomal recessive inheritance pattern.
  • MUTYH-driven polyposis with upper and lower gastrointestinal adenoma involvement.
Show evidence (1 reference)
PMID:19822006 SUPPORT Human Clinical
"In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract."
Supports MAP as an important differential with distinct inheritance and gene etiology.
Peutz-Jeghers syndrome Not Yet Curated MONDO:0008280
Overlapping Features Peutz-Jeghers syndrome is a hereditary gastrointestinal polyposis syndrome that can overlap clinically with polyposis presentations but differs in polyp histology and syndromic features.
Distinguishing Features
  • Predominantly hamartomatous polyps rather than classic adenomatous polyposis pattern.
  • Distinct syndromic phenotype with mucocutaneous pigmentation.
Show evidence (1 reference)
PMID:19822006 SUPPORT Human Clinical
"Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
Explicitly lists Peutz-Jeghers syndrome as a differential diagnosis for FAP.
Juvenile polyposis syndrome MONDO:0017380
Overlapping Features Juvenile polyposis syndrome can present with multiple gastrointestinal polyps and should be distinguished from classic adenomatous polyposis.
Distinguishing Features
  • Juvenile/hamartomatous polyp predominance rather than diffuse adenomatous phenotype.
  • Distinct hereditary syndrome context and risk framework.
Show evidence (1 reference)
PMID:19822006 SUPPORT Human Clinical
"Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
Supports juvenile polyposis-spectrum disorders as a differential in polyposis workups.
Lynch syndrome MONDO:0005835
Overlapping Features Lynch syndrome is a hereditary colorectal cancer syndrome with overlapping cancer risk context but typically without the classic profuse adenomatous polyposis phenotype.
Distinguishing Features
  • Hereditary mismatch-repair cancer syndrome rather than classic high-burden adenomatous polyposis.
  • Nonpolyposis phenotype context is a key distinction from classic FAP.
Show evidence (1 reference)
PMID:19822006 SUPPORT Human Clinical
"Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
Explicitly identifies Lynch syndrome as a differential diagnosis to exclude.
📊

Related Datasets

2
Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis DOI:10.1038/s43018-024-00831-z
Deep multiomic profiling resource spanning normal mucosa, benign polyps, and dysplastic polyps in classic FAP, used to characterize early precancer transitions.
human PROTEOMICS n=93
colorectal mucosal and polyp tissue
Conditions: classic familial adenomatous polyposis colorectal precancer progression
Show evidence (1 reference)
DOI:10.1038/s43018-024-00831-z SUPPORT Human Clinical
"We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP."
Supports sample composition and multiomic design of this FAP dataset resource.
Evolutionary history of adenomas to colorectal cancer in FAP families DOI:10.3389/fgene.2024.1391851
Multi-region whole-exome sequencing dataset from adenomas and carcinomas in FAP families, used for phylogenetic reconstruction of adenoma-to-carcinoma evolution.
human WES n=36
colorectal adenoma and carcinoma tissue
Conditions: classic familial adenomatous polyposis colorectal adenocarcinoma
Show evidence (1 reference)
DOI:10.3389/fgene.2024.1391851 SUPPORT Human Clinical
"Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families."
Supports cohort composition and WES dataset scope for evolutionary analysis.
🔬

Clinical Trials

4
NCT06545526 PHASE_III RECRUITING
Randomized open-label trial comparing celecoxib monotherapy versus celecoxib plus metformin for chemoprevention of colorectal and duodenal polyps in FAP.
Target Phenotypes: Large intestinal polyposis ↗ Small intestinal polyposis ↗
Show evidence (1 reference)
clinicaltrials:NCT06545526 SUPPORT Human Clinical
"We devised a randomized, open-label, comparative study to evaluate the effect of combination of celecoxib and metformin on polyps of colorectum and duodenum in FAP patients."
Supports trial design and intervention scope for ongoing combination chemoprevention.
NCT01725490 PHASE_II COMPLETED
Double-blind randomized trial evaluating metformin for reduction of colorectal and duodenal polyp burden in non-diabetic FAP.
Target Phenotypes: Large intestinal polyposis ↗ Small intestinal polyposis ↗
Show evidence (1 reference)
clinicaltrials:NCT01725490 SUPPORT Human Clinical
"The investigators devised a double-blind randomized controlled trial to evaluate the effect of metformin on polyps of colorectum and duodenum in non-diabetic FAP patients."
Supports trial objective and target lesion sites.
NCT02961374 PHASE_II COMPLETED
Phase II trial testing weekly erlotinib to reduce duodenal polyp burden in FAP patients at risk of progression.
Target Phenotypes: Small intestinal polyposis ↗
Show evidence (1 reference)
clinicaltrials:NCT02961374 SUPPORT Human Clinical
"This phase II trial studies the side effects of erlotinib hydrochloride and how well it works in reducing duodenal polyp burden in patients with familial adenomatous polyposis at risk of developing colon cancer."
Supports trial phase, intervention, and duodenal burden endpoint.
NCT01483144 PHASE_III COMPLETED
Randomized double-blind phase III trial comparing eflornithine plus sulindac versus monotherapy arms for delay of FAP-related progression.
Target Phenotypes: Large intestinal polyposis ↗ Small intestinal polyposis ↗
Show evidence (1 reference)
clinicaltrials:NCT01483144 SUPPORT Human Clinical
"The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event."
Supports trial objective and progression-delay endpoint.
{ }

Source YAML

click to show 
name: Classic Familial Adenomatous Polyposis
creation_date: '2026-03-01T18:54:36Z'
updated_date: '2026-03-02T17:38:45Z'
category: Mendelian
description: >-
  Classic familial adenomatous polyposis (classic FAP) is an autosomal dominant
  APC-associated polyposis syndrome characterized by extensive colorectal adenoma
  burden beginning early in life and very high colorectal cancer risk without
  definitive preventive management. Disease progression follows an APC-initiated
  adenoma-to-carcinoma trajectory with cooperative WNT, PI3K/mTOR, and genomic
  instability mechanisms, while upper gastrointestinal and extracolonic disease
  manifestations remain clinically important across adulthood.
synonyms:
- Classic FAP
- familial polyposis coli
- Familial adenomatous polyposis (classic form)
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Polyposis Syndrome
notes: >-
  Classic FAP management integrates APC genotype-phenotype context with lifelong
  colorectal and upper gastrointestinal surveillance; extracolonic findings
  (such as CHRPE, osteomas, desmoid disease, and cutaneous cysts) can provide
  early diagnostic clues and affect risk-stratified care planning.
disease_term:
  preferred_term: classic familial adenomatous polyposis
  term:
    id: MONDO:0021055
    label: classic familial adenomatous polyposis
classifications:
  harrisons_chapter:
  - classification_value: cancer
    evidence:
    - reference: PMID:37119510
      reference_title: "Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
      explanation: Supports placement within cancer-focused clinical classification frameworks due near-inevitable malignant progression without definitive prevention.
  - classification_value: hereditary disease
    evidence:
    - reference: DOI:10.1055/s-0043-1767707
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
      explanation: Supports hereditary disease classification based on germline APC inheritance biology.
parents:
- familial adenomatous polyposis
prevalence:
- population: Clinically ascertained FAP cohorts
  percentage: birth incidence about 1 in 8,300
  notes: >-
    Published epidemiology for familial adenomatous polyposis usually combines
    classic and attenuated APC-associated disease, but the major historical
    incidence estimates are driven by clinically recognized classic FAP.
    Orphanet review data report a birth incidence of about 1 in 8,300 and
    European prevalence of 1 in 11,300-37,600, while Finnish registry data
    showed prevalence rising to 26.3 per million with systematic family
    screening.
  evidence:
  - reference: PMID:19822006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600."
    explanation: This Orphanet review provides the standard incidence-at-birth and European prevalence estimates for clinically recognized FAP.
  - reference: PMID:1314763
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of FAP was 0.62 to 2.38 per million and the prevalence increased steadily from 0.88 to 26.3 million during the study period suggesting improving prognosis."
    explanation: Registry-based Finnish epidemiology provides an independent clinically ascertained incidence/prevalence range for FAP under active family screening.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >-
    Classic FAP is inherited in an autosomal dominant pattern due to pathogenic
    germline APC variants, with variable disease severity and extracolonic
    manifestations.
  evidence:
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
    explanation: The abstract directly supports autosomal dominant APC-mediated inheritance in FAP.
progression:
- phase: Early adenoma phase
  age_range: adolescence to young adulthood
  notes: >-
    Classic FAP manifests with a high adenoma burden early in life, establishing
    an extended precancer phase requiring close surveillance.
  evidence:
  - reference: DOI:10.1038/s43018-024-00831-z
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC)."
    explanation: This supports the early, high-burden premalignant adenoma phase.
- phase: Adenoma to carcinoma transition
  notes: >-
    Without effective preventive intervention, adenomas progress through staged
    molecular evolution to colorectal carcinoma.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC)."
    explanation: This explicitly supports inevitable progression from polyps to CRC when untreated.
- phase: Advanced cancer risk without definitive management
  notes: >-
    CRC risk approaches certainty by mid-adulthood in unmanaged disease, which
    drives recommendations for early definitive colorectal risk-reduction strategies.
  evidence:
  - reference: PMID:37119510
    reference_title: "Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
    explanation: This supports near-universal CRC progression risk by age and the clinical rationale for early colectomy.
pathophysiology:
- name: Germline APC loss-of-function predisposition
  description: >-
    Germline pathogenic APC variation establishes a constitutional tumor
    suppressor deficit that predisposes colonic and rectal epithelium to
    adenoma development.
  gene:
    preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: rectum
    term:
      id: UBERON:0001052
      label: rectum
  downstream:
  - target: APC-initiated WNT pathway activation
    description: Loss of APC function permits canonical WNT pathway activation.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.3389/fgene.2024.1391851
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN."
      explanation: Supports the specific causal edge from APC-initiated disease biology to WNT activation.
  evidence:
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
    explanation: Supports APC germline mutation as the initiating pathogenic event in FAP.
  - reference: PMID:28668823
    reference_title: "Desmoid Tumors in Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is a cancer syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene."
    explanation: Adds independent support that germline APC mutation is the core inherited initiating event.
- name: APC-initiated WNT pathway activation
  description: >-
    APC-initiated tumorigenesis proceeds through activation of canonical WNT
    signaling as an early mechanistic axis in FAP carcinogenesis.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  downstream:
  - target: Epithelial hyperproliferation
    description: WNT activation increases proliferative drive in intestinal epithelium.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1038/s43018-024-00831-z
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins."
      explanation: Supports proliferative expansion as a key downstream event during early precancer transitions.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN."
    explanation: Supports the APC-to-WNT mechanistic step in progression.
- name: Epithelial hyperproliferation
  description: >-
    Precancer transitions in classic FAP involve strong pro-growth molecular
    remodeling and expanded epithelial proliferative signaling.
  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 initiation
    description: Sustained epithelial proliferation drives early adenoma formation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19822006
      reference_title: "Familial adenomatous polyposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life."
      explanation: Supports progression from epithelial proliferative dysregulation to adenoma formation.
  evidence:
  - reference: DOI:10.1038/s43018-024-00831-z
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation."
    explanation: Supports a broad, early molecular expansion program during precancer progression in FAP.
- name: Adenoma initiation
  description: >-
    Early adenomatous lesions arise in colorectal mucosa and provide the
    substrate for subsequent lesion expansion and malignant progression.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: rectum
    term:
      id: UBERON:0001052
      label: rectum
  downstream:
  - target: PI3K/mTOR co-activation in adenomatous lesions
    description: Established adenomas acquire cooperative PI3K/mTOR pathway activation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Additional oncogenic and microenvironmental pathway cooperation
    evidence:
    - reference: DOI:10.1186/s12967-024-05305-5
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs."
      explanation: Supports pathway cooperation in established FAP adenomatous lesions.
  - target: Colorectal polyposis
    description: Repeated adenoma initiation and persistence produce high-burden colorectal polyposis.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1038/s43018-024-00831-z
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC)."
      explanation: Supports accumulation of numerous premalignant adenomas as the polyposis phenotype.
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life."
    explanation: Supports adenoma initiation as a discrete early disease event.
- name: PI3K/mTOR co-activation in adenomatous lesions
  description: >-
    FAP lesions demonstrate PI3K/mTOR pathway co-activation alongside WNT
    dysregulation, consistent with pathway cooperation during progression.
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Microbiome-associated pathway modulation
    description: WNT and mTOR pathway activity tracks with specific microbial signatures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Host-microbiome and inflammatory signaling interactions
    evidence:
    - reference: DOI:10.1186/s12967-024-05305-5
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment."
      explanation: Supports microbiome-linked modulation associated with WNT/PI3K/mTOR pathway derangement.
  - target: Genomic instability accumulation across adenoma grades
    description: Co-activated signaling supports progression toward genomically unstable advanced lesions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fgene.2024.1391851
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability."
      explanation: Supports downstream emergence of genomic instability in progressing FAP lesions.
  evidence:
  - reference: DOI:10.1186/s12967-024-05305-5
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs."
    explanation: Directly supports concurrent WNT and PI3K/mTOR pathway hyperactivation in FAP lesions.
- name: Microbiome-associated pathway modulation
  description: >-
    Distinct fecal and lesion-associated microbial signatures correlate with WNT
    and mTOR pathway readouts in FAP, indicating microbiome-linked modulation of
    progression biology.
  downstream:
  - target: Genomic instability accumulation across adenoma grades
    description: Microbiome-linked signaling perturbation may contribute to heterogeneous evolutionary trajectories.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1186/s12967-024-05305-5
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment."
      explanation: Supports an indirect microbiome-pathway relationship with progression biology.
  evidence:
  - reference: DOI:10.1186/s12967-024-05305-5
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment."
    explanation: Supports mechanistic coupling between pathway derangement and microbiota signatures in FAP.
- name: Genomic instability accumulation across adenoma grades
  description: >-
    Adenoma evolution in classic FAP is marked by increasing chromosomal and DNA
    repair instability features from tubular adenoma to villous adenoma to
    carcinoma.
  biological_processes:
  - preferred_term: chromosome organization
    modifier: DYSREGULATED
    term:
      id: GO:0051276
      label: chromosome organization
  - preferred_term: DNA repair
    modifier: DYSREGULATED
    term:
      id: GO:0006281
      label: DNA repair
  downstream:
  - target: TP53 driver emergence in advanced adenomas
    description: Accumulated genomic instability promotes emergence of carcinoma-driving alterations.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.3389/fgene.2024.1391851
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
      explanation: Supports the direct transition edge from genomic instability to TP53-dominant carcinoma progression.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, a progressive increase in the HRD score (a measure of “genomic scars”) was observed from tubular adenomas to villous adenomas and ultimately to carcinomas."
    explanation: Supports stepwise accumulation of genomic instability through progression stages.
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability."
    explanation: Supports CIN and DNA repair disruption as central progression features.
- name: TP53 driver emergence in advanced adenomas
  description: >-
    Advanced FAP lesions accumulate TP53 driver events that prime transition to
    invasive carcinoma.
  downstream:
  - target: Adenoma-to-carcinoma transition
    description: TP53 driver acquisition promotes malignant transition of advanced adenomas.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.3389/fgene.2024.1391851
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
      explanation: Supports TP53 driver emergence as a discrete transition-priming event.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
    explanation: Supports TP53 as a key driver event in advanced adenoma evolution.
- name: Adenoma-to-carcinoma transition
  description: >-
    Advanced adenomas progress to invasive colorectal carcinoma in the absence
    of effective preventive intervention.
  downstream:
  - target: Colorectal cancer
    description: Malignant transition culminates in invasive colorectal cancer.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.3389/fgene.2024.1391851
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC)."
      explanation: Supports direct malignant progression from adenomatous disease to colorectal cancer.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC)."
    explanation: Supports adenoma-to-carcinoma transition as a discrete late-stage event.
phenotypes:
- name: Colorectal polyposis
  category: Gastrointestinal
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Classic FAP is defined by extensive colorectal adenoma burden, typically with
    hundreds of premalignant lesions.
  phenotype_term:
    preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
  evidence:
  - reference: DOI:10.1038/s43018-024-00831-z
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC)."
    explanation: Supports hallmark high-burden colorectal polyposis.
- name: Colorectal cancer
  category: Neoplastic
  frequency: OBLIGATE
  description: >-
    In unmanaged disease, colorectal cancer risk is extremely high and often
    approaches certainty by mid-adulthood.
  phenotype_term:
    preferred_term: Colon cancer
    term:
      id: HP:0003003
      label: Colon cancer
  evidence:
  - reference: PMID:37119510
    reference_title: "Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
    explanation: Supports very high CRC risk in classic FAP without definitive prevention.
- name: Duodenal polyposis and neoplasia risk
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Upper gastrointestinal involvement, including duodenal adenomas and related
    cancer risk, is a major ongoing management issue.
  phenotype_term:
    preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: PMID:35636921
    reference_title: "Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer."
    explanation: Supports frequent and clinically significant duodenal disease in FAP.
  - reference: PMID:39046601
    reference_title: "Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance."
    explanation: Adds population-level evidence for high duodenal disease burden and surveillance relevance.
- name: Desmoid tumor susceptibility
  category: Neoplastic
  frequency: FREQUENT
  description: >-
    Desmoid risk influences timing and type of surgery and contributes to
    heterogeneity in clinical management.
  phenotype_term:
    preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  evidence:
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed."
    explanation: Supports desmoid risk as a clinically relevant disease manifestation and management modifier.
  - reference: PMID:39729982
    reference_title: "Adenomatous Polyposis Coli Gene Mutations, Risk Factors, and Long-term Outcomes Associated With Desmoid Tumors in Patients With Familial Adenomatous Polyposis After Colectomy in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of desmoid tumor development was 30.3% in 66 patients."
    explanation: Adds quantitative cohort evidence for substantial desmoid susceptibility after colectomy.
- name: Osteomas
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Osseous anomalies including osteomas are part of extracolonic disease
    expression and can precede overt intestinal presentation.
  phenotype_term:
    preferred_term: Osteoma
    term:
      id: HP:0100246
      label: Osteoma
  evidence:
  - reference: DOI:10.3390/ijms25158189
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyses of our cases and the mutations available in the literature with these manifestations revealed that mutations in the N-terminal region (amino acids 1–~1000) of the protein are more frequently associated with only osseous anomalies, whereas dental manifestations are more prevalent in mutations in the middle region (amino acids 1000–~2100)."
    explanation: Supports APC-associated osseous phenotypes including osteoma-predominant extracolonic disease.
- name: Dental anomalies
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Dental abnormalities may precede intestinal polyposis and provide an early
    extracolonic diagnostic clue.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: DOI:10.3390/ijms25158189
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since dental abnormalities often precede intestinal polyposis, dentists have a crucial role in the early identification of patients at risk."
    explanation: Supports dental anomalies as an early and clinically actionable phenotype in APC-associated disease.
- name: Congenital hypertrophy of retinal pigment epithelium
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    CHRPE lesions are a common extracolonic manifestation in classic FAP and are
    clinically useful as an early, non-invasive screening marker in at-risk
    individuals.
  phenotype_term:
    preferred_term: Congenital hypertrophy of retinal pigment epithelium
    term:
      id: HP:0007649
      label: Congenital hypertrophy of retinal pigment epithelium
  evidence:
  - reference: PMID:31525261
    reference_title: "In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The percentage of FAP patients with CHRPE was found to be 80.00%, whereas the percentage of at-risk patients with CHRPE was 31.12%."
    explanation: Supports high prevalence of CHRPE in classic FAP and its practical value in screening at-risk cohorts.
  - reference: PMID:35321042
    reference_title: "Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHRPE was found to be a non-invasive, rapid, early phenotypical screening marker of FAP."
    explanation: Supports diagnostic utility of CHRPE as an early phenotypic marker.
- name: Epidermoid cysts (sebaceous cyst phenotype)
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Cutaneous epidermoid/sebaceous cyst manifestations are part of the
    Gardner-spectrum extracolonic phenotype in APC-associated disease.
  phenotype_term:
    preferred_term: Epidermoid cyst
    term:
      id: HP:0200040
      label: Epidermoid cyst
  evidence:
  - reference: PMID:16411234
    reference_title: "Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sebaceous cysts were reported in 51% of the patients, and their APC mutations were evenly distributed in the gene with no particular hotspot."
    explanation: Supports frequent cystic cutaneous manifestations in APC-associated FAP/Gardner-spectrum disease.
biochemical:
- name: Reduced p-S6 signal after metformin exposure
  presence: Reduced in resected colon polyps after treatment
  notes: >-
    Metformin-treated lesions showed lower phosphorylated S6 signal, consistent
    with mTOR pathway modulation even when macroscopic polyp regression endpoints
    were not met.
  evidence:
  - reference: PMID:33509804
    reference_title: "The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm."
    explanation: Supports measurable mTOR-pathway biochemical modulation in treated polyps.
genetic:
- name: APC
  association: Germline pathogenic loss-of-function variants
  gene_term:
    preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: DOI:10.1055/s-0043-1767707
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
      explanation: Supports autosomal dominant inheritance within the APC-associated genetic context.
  notes: >-
    APC is the principal causal gene in classic FAP, with genotype-phenotype
    effects on disease severity and extracolonic manifestations.
  evidence:
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum."
    explanation: Supports APC as the germline causal driver of disease.
- name: TP53 and cooperating progression drivers
  association: Somatic progression-associated alterations
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  notes: >-
    Advanced progression involves TP53 and other CIN/DDR-associated drivers that
    accumulate across adenoma grades toward carcinoma.
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas."
    explanation: Supports a TP53-dominant transition mechanism in advanced progression.
treatments:
- name: Prophylactic colectomy
  description: >-
    Definitive colorectal cancer risk reduction in classic FAP is centered on
    timely colectomy/proctocolectomy, individualized by phenotype and risk context.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
    qualifiers:
    - predicate:
        preferred_term: surgical procedure
        term:
          id: NCIT:C15329
          label: Surgical Procedure
      value:
        preferred_term: colectomy
        term:
          id: NCIT:C15209
          label: Colectomy
    - predicate:
        preferred_term: surgical procedure
        term:
          id: NCIT:C15329
          label: Surgical Procedure
      value:
        preferred_term: proctocolectomy
        term:
          id: NCIT:C51635
          label: Proctocolectomy
  evidence:
  - reference: PMID:37119510
    reference_title: "Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment."
    explanation: Supports colectomy as a core preventive intervention in classic FAP.
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, proctocolectomy is recommended for FAP patients at the age of 20s."
    explanation: Supports guideline-aligned timing of prophylactic surgery.
- name: Endoscopic surveillance
  description: >-
    Longitudinal endoscopic surveillance remains essential for upper
    gastrointestinal and post-colectomy lower tract risk management.
  treatment_term:
    preferred_term: colonoscopy
    term:
      id: MAXO:0001184
      label: colonoscopy
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: colonoscopy
        term:
          id: NCIT:C16450
          label: Colonoscopy
  evidence:
  - reference: DOI:10.1055/s-0043-1770384
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy)."
    explanation: Supports intensive endoscopic screening as a core prevention strategy.
  - reference: PMID:37119510
    reference_title: "Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood."
    explanation: Supports lifelong endoscopic surveillance needs after surgical management.
- name: NSAID and COX-2 inhibitor chemoprevention
  description: >-
    NSAID-based chemoprevention is used as an adjunctive approach but evidence
    remains heterogeneous and not sufficient to replace surgery/surveillance.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: sulindac
        term:
          id: NCIT:C850
          label: Sulindac
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: celecoxib
        term:
          id: NCIT:C1728
          label: Celecoxib
  target_mechanisms:
  - target: Adenoma initiation
    treatment_effect: MODULATES
    description: Adjunctive pharmacologic suppression of adenoma-promoting pathways.
    evidence:
    - reference: DOI:10.1055/s-0043-1770384
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater."
      explanation: Supports mechanism-level use of adjunct pharmacologic modulation in high-risk hereditary CRC syndromes.
  evidence:
  - reference: DOI:10.1055/s-0043-1770384
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater."
    explanation: Supports adjunctive chemoprevention strategy in hereditary cancer settings including FAP.
  - reference: DOI:10.1055/s-0043-1770384
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "However, to date only few compounds have been found to be effective, safe, and tolerable for widespread use."
    explanation: Supports a cautious interpretation of chemoprevention efficacy and tolerability.
- name: Metformin-based chemoprevention
  description: >-
    Metformin remains investigational in FAP, with mixed efficacy signals across
    studies and evidence of pathway-level biologic activity.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: metformin
        term:
          id: NCIT:C61612
          label: Metformin
  target_mechanisms:
  - target: PI3K/mTOR co-activation in adenomatous lesions
    treatment_effect: INHIBITS
    description: Metformin is investigated as an mTOR-modulating intervention.
    evidence:
    - reference: PMID:33509804
      reference_title: "The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Colon polyps removed from the metformin-treated patients showed significantly lower mTOR signal (p-S6) expression than those from patients in the placebo arm."
      explanation: Supports pathway-level inhibition of mTOR signaling by metformin in treated lesions.
  evidence:
  - reference: DOI:10.1186/s13023-024-03064-6
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One-year metformin therapy for FAP is safe and effective, potentially mediated by modulating the intestinal flora."
    explanation: Supports favorable efficacy/safety signal in one recent clinical study.
  - reference: PMID:33509804
    reference_title: "The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A 7-month metformin treatment (500 mg or 1,500 mg) did not reduce the number or size of polyps in the colorectum or duodenum of FAP patients as compared to placebo."
    explanation: Supports conflicting trial evidence showing no significant lesion-regression endpoint benefit.
- name: Erlotinib chemoprevention strategy
  description: >-
    EGFR-targeted chemoprevention with weekly erlotinib can reduce duodenal
    burden but adverse events remain common.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: erlotinib
        term:
          id: NCIT:C65530
          label: Erlotinib
  evidence:
  - reference: PMID:35636921
    reference_title: "Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001)."
    explanation: Supports clinical efficacy for reducing duodenal polyp burden.
  - reference: PMID:35636921
    reference_title: "Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention."
    explanation: Supports efficacy with important tolerability tradeoffs.
- name: Eflornithine plus sulindac combination
  description: >-
    Combination DFMO/sulindac has been tested for progression delay, but primary
    efficacy over monotherapy has not been clearly demonstrated.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: eflornithine
        term:
          id: NCIT:C226
          label: Eflornithine
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: sulindac
        term:
          id: NCIT:C850
          label: Sulindac
  evidence:
  - reference: PMID:32905675
    reference_title: "Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone."
    explanation: Supports limited incremental efficacy of combination therapy in the primary trial analysis.
- name: Genetic counseling and hereditary risk management
  description: >-
    Risk counseling and genetic assessment are integral to management of
    hereditary gastrointestinal cancer syndromes, including APC-associated
    polyposis families.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: DOI:10.3390/cimb46070385
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants."
    explanation: Supports inclusion of structured genetic counseling as a core management component.
diagnosis:
- name: Colonoscopic and upper GI surveillance strategy
  description: >-
    Diagnosis and longitudinal management rely on intensive endoscopic detection
    and characterization of colorectal and upper GI polyp burden.
  diagnosis_term:
    preferred_term: colonoscopy
    term:
      id: MAXO:0001184
      label: colonoscopy
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: colonoscopy
        term:
          id: NCIT:C16450
          label: Colonoscopy
  evidence:
  - reference: DOI:10.1055/s-0043-1770384
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy)."
    explanation: Supports intensive endoscopic surveillance as a core diagnostic-management approach.
  - reference: PMID:39046601
    reference_title: "Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance."
    explanation: Adds nationwide cohort evidence reinforcing ongoing upper GI endoscopic surveillance.
- name: Genotype-informed surgical risk stratification
  description: >-
    APC genotype-phenotype relationships are integrated into decision-making for
    timing and extent of surgery.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: genetic testing
        term:
          id: NCIT:C15709
          label: Genetic Testing
  evidence:
  - reference: DOI:10.1055/s-0043-1767707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various genetic variants have been confirmed to be associated with corresponding FAP phenotypes, which play important roles in the diagnosis and surgical treatment of FAP."
    explanation: Supports genotype-informed diagnosis and management planning.
differential_diagnoses:
- name: Attenuated familial adenomatous polyposis
  description: >-
    AFAP shares APC-related adenomatous polyposis biology with classic FAP but
    usually presents with lower adenoma burden and later onset.
  distinguishing_features:
  - Usually 10 to 100 colorectal adenomas rather than hundreds to thousands.
  - Later age of adenoma appearance and comparatively lower colorectal cancer risk.
  disease_term:
    preferred_term: attenuated familial adenomatous polyposis
    term:
      id: MONDO:0016362
      label: attenuated familial adenomatous polyposis
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk."
    explanation: Supports AFAP as a key differential diagnosis and provides distinguishing clinical criteria.
  - reference: PMID:34775416
    reference_title: "Attenuated Familial Adenomatous Polyposis: A Phenotypic Diagnosis but Obsolete Term?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Attenuated familial adenomatous polyposis is characterised by low number (≤100) and delayed development of colorectal adenomas."
    explanation: Provides additional modern cohort-based support for AFAP low-count and delayed-onset distinguishing features.
- name: MUTYH-associated polyposis
  description: >-
    MAP can phenocopy adenomatous polyposis but differs from classic FAP by
    recessive inheritance and MUTYH etiology.
  distinguishing_features:
  - Autosomal recessive inheritance pattern.
  - MUTYH-driven polyposis with upper and lower gastrointestinal adenoma involvement.
  disease_term:
    preferred_term: MUTYH-associated polyposis
    term:
      id: MONDO:0012041
      label: familial adenomatous polyposis 2
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract."
    explanation: Supports MAP as an important differential with distinct inheritance and gene etiology.
- name: Peutz-Jeghers syndrome
  description: >-
    Peutz-Jeghers syndrome is a hereditary gastrointestinal polyposis syndrome
    that can overlap clinically with polyposis presentations but differs in
    polyp histology and syndromic features.
  distinguishing_features:
  - Predominantly hamartomatous polyps rather than classic adenomatous polyposis pattern.
  - Distinct syndromic phenotype with mucocutaneous pigmentation.
  disease_term:
    preferred_term: Peutz-Jeghers syndrome
    term:
      id: MONDO:0008280
      label: Peutz-Jeghers syndrome
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
    explanation: Explicitly lists Peutz-Jeghers syndrome as a differential diagnosis for FAP.
- name: Juvenile polyposis syndrome
  description: >-
    Juvenile polyposis syndrome can present with multiple gastrointestinal
    polyps and should be distinguished from classic adenomatous polyposis.
  distinguishing_features:
  - Juvenile/hamartomatous polyp predominance rather than diffuse adenomatous phenotype.
  - Distinct hereditary syndrome context and risk framework.
  disease_term:
    preferred_term: juvenile polyposis syndrome
    term:
      id: MONDO:0017380
      label: juvenile polyposis syndrome
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
    explanation: Supports juvenile polyposis-spectrum disorders as a differential in polyposis workups.
- name: Lynch syndrome
  description: >-
    Lynch syndrome is a hereditary colorectal cancer syndrome with overlapping
    cancer risk context but typically without the classic profuse adenomatous
    polyposis phenotype.
  distinguishing_features:
  - Hereditary mismatch-repair cancer syndrome rather than classic high-burden adenomatous polyposis.
  - Nonpolyposis phenotype context is a key distinction from classic FAP.
  disease_term:
    preferred_term: Lynch syndrome
    term:
      id: MONDO:0005835
      label: Lynch syndrome
  evidence:
  - reference: PMID:19822006
    reference_title: "Familial adenomatous polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome)."
    explanation: Explicitly identifies Lynch syndrome as a differential diagnosis to exclude.
clinical_trials:
- name: NCT06545526
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Randomized open-label trial comparing celecoxib monotherapy versus
    celecoxib plus metformin for chemoprevention of colorectal and duodenal
    polyps in FAP.
  target_phenotypes:
  - preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
  - preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: clinicaltrials:NCT06545526
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We devised a randomized, open-label, comparative study to evaluate the effect of combination of celecoxib and metformin on polyps of colorectum and duodenum in FAP patients."
    explanation: Supports trial design and intervention scope for ongoing combination chemoprevention.
- name: NCT01725490
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Double-blind randomized trial evaluating metformin for reduction of
    colorectal and duodenal polyp burden in non-diabetic FAP.
  target_phenotypes:
  - preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
  - preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: clinicaltrials:NCT01725490
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The investigators devised a double-blind randomized controlled trial to evaluate the effect of metformin on polyps of colorectum and duodenum in non-diabetic FAP patients."
    explanation: Supports trial objective and target lesion sites.
- name: NCT02961374
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase II trial testing weekly erlotinib to reduce duodenal polyp burden in
    FAP patients at risk of progression.
  target_phenotypes:
  - preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: clinicaltrials:NCT02961374
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This phase II trial studies the side effects of erlotinib hydrochloride and how well it works in reducing duodenal polyp burden in patients with familial adenomatous polyposis at risk of developing colon cancer."
    explanation: Supports trial phase, intervention, and duodenal burden endpoint.
- name: NCT01483144
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomized double-blind phase III trial comparing eflornithine plus
    sulindac versus monotherapy arms for delay of FAP-related progression.
  target_phenotypes:
  - preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
  - preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: clinicaltrials:NCT01483144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event."
    explanation: Supports trial objective and progression-delay endpoint.
datasets:
- accession: DOI:10.1038/s43018-024-00831-z
  title: Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis
  description: >-
    Deep multiomic profiling resource spanning normal mucosa, benign polyps, and
    dysplastic polyps in classic FAP, used to characterize early precancer
    transitions.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_types:
  - preferred_term: colorectal mucosal and polyp tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 93
  conditions:
  - classic familial adenomatous polyposis
  - colorectal precancer progression
  evidence:
  - reference: DOI:10.1038/s43018-024-00831-z
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP."
    explanation: Supports sample composition and multiomic design of this FAP dataset resource.
- accession: DOI:10.3389/fgene.2024.1391851
  title: Evolutionary history of adenomas to colorectal cancer in FAP families
  description: >-
    Multi-region whole-exome sequencing dataset from adenomas and carcinomas in
    FAP families, used for phylogenetic reconstruction of adenoma-to-carcinoma
    evolution.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WES
  sample_types:
  - preferred_term: colorectal adenoma and carcinoma tissue
    term:
      id: UBERON:0001155
      label: colon
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  sample_count: 36
  conditions:
  - classic familial adenomatous polyposis
  - colorectal adenocarcinoma
  evidence:
  - reference: DOI:10.3389/fgene.2024.1391851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families."
    explanation: Supports cohort composition and WES dataset scope for evolutionary analysis.
references:
- reference: DOI:10.1038/s43018-024-00831-z
  title: Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis
  findings: []
- reference: DOI:10.1055/s-0043-1767707
  title: Update on Surgical Management of FAP
  findings: []
- reference: DOI:10.1055/s-0043-1770384
  title: Chemoprevention in Inherited Colorectal Cancer Syndromes
  findings: []
- reference: DOI:10.1186/s12967-024-05305-5
  title: Interplay between WNT/PI3K-mTOR axis and the microbiota in APC-driven colorectal carcinogenesis data from a pilot study and possible implications for CRC prevention
  findings: []
- reference: DOI:10.1186/s13023-024-03064-6
  title: Clinical efficacy of metformin in familial adenomatous polyposis and the effect of intestinal flora
  findings: []
- reference: DOI:10.3389/fgene.2024.1391851
  title: Evolutionary history of adenomas to colorectal cancer in FAP families
  findings: []
- reference: DOI:10.3390/ijms25158189
  title: Rare Germline Variants in the Adenomatous Polyposis Coli Gene Associated with Dental and Osseous Anomalies
  findings: []
- reference: DOI:10.3390/cimb46070385
  title: 'Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes'
  findings: []
- reference: PMID:19822006
  title: Familial adenomatous polyposis.
  findings: []
- reference: PMID:16411234
  title: 'Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts.'
  findings: []
- reference: PMID:28668823
  title: Desmoid Tumors in Familial Adenomatous Polyposis.
  findings: []
- reference: PMID:31525261
  title: 'In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: A systematic review.'
  findings: []
- reference: PMID:32905675
  title: Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.
  findings: []
- reference: PMID:33509804
  title: The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis.
  findings: []
- reference: PMID:34775416
  title: 'Attenuated Familial Adenomatous Polyposis: A Phenotypic Diagnosis but Obsolete Term?'
  findings: []
- reference: PMID:35636921
  title: Phase II trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis.
  findings: []
- reference: PMID:37119510
  title: Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome.
  findings: []
- reference: PMID:39046601
  title: Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up.
  findings: []
- reference: PMID:39729982
  title: Adenomatous Polyposis Coli Gene Mutations, Risk Factors, and Long-term Outcomes Associated With Desmoid Tumors in Patients With Familial Adenomatous Polyposis After Colectomy in Japan.
  findings: []
- reference: PMID:35321042
  title: 'Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) as a Screening Marker for Familial Adenomatous Polyposis (FAP): Systematic Literature Review and Screening Recommendations.'
  findings: []
- reference: clinicaltrials:NCT01483144
  title: Phase III Trial of the Safety and Efficacy of Eflornithine Combined With Sulindac Compared to Eflornithine, Sulindac as Single Agents in Patients With Familial Adenomatous Polyposis
  findings: []
- reference: clinicaltrials:NCT01725490
  title: The Chemopreventive Effect of Metformin in Patients With Familial Adenomatous Polyposis Double Blinded Randomized Controlled Study
  findings: []
- reference: clinicaltrials:NCT02961374
  title: Phase II Trial of Weekly Erlotinib Dosing to Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis
  findings: []
- reference: clinicaltrials:NCT06545526
  title: The Chemopreventive Effect of Celecoxib Monotherapy Versus Combination of Celecoxib and Metformin in Patients With Familial Adenomatous Polyposis a Pilot Randomized Open-label Comparative Study
  findings: []