1. Disease Information

1.1 Overview (definition and current understanding)

Classic familial adenomatous polyposis (classic FAP) is an autosomal dominant hereditary colorectal cancer predisposition syndrome characterized by extensive colorectal adenomatous polyposis (classically ≥100 cumulative adenomas) with near-certain progression to colorectal cancer (CRC) by mid-adulthood without prophylactic colorectal surgery. A widely used operational definition in contemporary cohorts is “more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene.” (karstensen2024endoscopicindicatorsin pages 1-2)

A recent review states that FAP is “marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC)” and emphasizes that screening/enrollment programs enable prophylactic surgery before CRC develops. (kyriakidis2023updatedperspectiveson pages 1-2)

1.2 Key identifiers

A structured set of identifiers extracted from authoritative disease knowledge resources (via OpenTargets) and recent literature is provided in the table artifact below.

Table: This table summarizes core identifiers, terminology, diagnostic thresholds, inheritance, causal gene, and recent epidemiology figures for classic familial adenomatous polyposis. It is designed to support structured disease knowledge base curation using only evidence available in the current context.

Key identifier highlights (evidence-backed): - MONDO: classic FAP = MONDO:0021055; related entities include familial adenomatous polyposis 1 (MONDO:0021056) and attenuated FAP (MONDO:0016362). (OpenTargets Search: familial adenomatous polyposis) - Orphanet: Familial adenomatous polyposis = Orphanet:733. (OpenTargets Search: familial adenomatous polyposis)

1.3 Synonyms / alternative names

Common names in current use include: - Familial adenomatous polyposis (FAP) / classic FAP (kyriakidis2023updatedperspectiveson pages 1-2, buki2024raregermlinevariants pages 1-2) - APC-associated polyposis (genotype-first framing) (kyriakidis2023updatedperspectiveson pages 2-4) - Gardner syndrome is described as an APC-associated variant with polyps plus osteomas and soft-tissue tumors. (buki2024raregermlinevariants pages 1-2)

1.4 Evidence provenance

The information in this report is derived from aggregated disease-level resources (OpenTargets) and aggregated research sources (reviews, cohort studies, trials) rather than EHR-only patient-level data, except for select case reports and institutional cohorts that were retrieved but not relied upon for core definitions. (OpenTargets Search: familial adenomatous polyposis, kyriakidis2023updatedperspectiveson pages 1-2, lin2024adrenaltumoursin pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): Germline loss-of-function variants in APC (adenomatous polyposis coli; tumor suppressor; regulator of β-catenin/Wnt signaling) are the major cause of classic FAP. (buki2024raregermlinevariants pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

A recent review explicitly describes APC as a tumor suppressor that “regulates β-catenin and Wnt signaling.” (kyriakidis2023updatedperspectiveson pages 1-2)

2.2 Risk factors

Genetic risk factors

• APC pathogenic variants (germline) are the causal risk factor for classic FAP; genotype–phenotype associations exist for some extracolonic features (not universally consistent across studies). (kyriakidis2023updatedperspectiveson pages 2-4, kyriakidis2023updatedperspectiveson pages 1-2)
• Post-zygotic/somatic mosaicism is an important diagnostic consideration in polyposis evaluation; one nationwide study used WGS and “screening for mosaicism in blood and/or adenomas” to improve detection of APC structural variants and mosaic APC pathogenic variants. (kyriakidis2023updatedperspectiveson pages 2-4)
• Risk modifiers (example: desmoid tumors): A review notes markedly increased desmoid risk for certain APC regions (e.g., “mutations beyond codon 1309 and 1444” associated with ~17-fold and ~12-fold higher desmoid risk). (kyriakidis2023updatedperspectiveson pages 2-4)

Environmental / iatrogenic risk factors

• Surgical/traumatic triggers for desmoids: desmoid tumor risk factors include “trauma” and “estrogens,” and distal APC variants/family history. (kumamoto2023recentadvancesand pages 1-2)

2.3 Protective factors

No robust, broadly accepted protective genetic variants or environmental protective factors specific to classic FAP were supported in the retrieved excerpts. Chemoprevention remains an active area of investigation with heterogeneous adoption and variable/limited efficacy. (kyriakidis2023updatedperspectiveson pages 10-12, aelvoet2023personalizedendoscopicsurveillance pages 1-2)

2.4 Gene–environment interactions

Direct gene–environment interaction evidence specific to classic FAP was limited in the retrieved excerpts, but desmoid tumor risk being influenced by trauma/surgery and estrogen exposure in the context of APC pathogenic variants is a clinically relevant example of interaction. (kumamoto2023recentadvancesand pages 1-2)

3. Phenotypes

3.1 Core gastrointestinal phenotype (classic)

Colorectal adenomatous polyposis - Phenotype type: clinical sign/endoscopic finding. - Typical onset: adolescence/young adulthood. One review notes polyps develop with a mean age around adolescence and diagnosis often occurs in early adulthood. (buki2024raregermlinevariants pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2) - Diagnostic threshold: typically ≥100 cumulative adenomas. (karstensen2024endoscopicindicatorsin pages 1-2, lin2024adrenaltumoursin pages 1-2)

Suggested HPO terms (examples): - Colonic polyposis: Intestinal polyposis (HP:0005220) - Colonic adenomas: Colonic adenomatous polyposis (commonly modeled; exact HPO label may vary by version)

3.2 Upper GI phenotypes (duodenum, stomach)

Duodenal adenomas / duodenal polyposis - A nationwide Danish cohort found that among those who underwent EGD, “59.2% presented with detectable duodenal adenomas.” (karstensen2024endoscopicindicatorsin pages 1-2) - In that cohort, duodenal adenocarcinoma developed in 3.4% (17/500), and 47% of those cancers were advanced at diagnosis. (karstensen2024endoscopicindicatorsin pages 1-2)

Suggested HPO terms: - Duodenal polyposis: Duodenal polyposis (HPO term availability depends on version) - Duodenal adenocarcinoma: Duodenal carcinoma (HPO term availability depends on version)

3.3 Extraintestinal manifestations (selected; frequencies from recent review excerpts)

A 2023 review summarizes several extracolonic manifestations with approximate frequencies/risks: - Congenital hypertrophy of retinal pigment epithelium (CHRPE): 60% (kyriakidis2023updatedperspectiveson pages 1-2) - Desmoid tumors: 20% (kyriakidis2023updatedperspectiveson pages 1-2); a dedicated desmoid review cites approximately 10–25% prevalence. (kumamoto2023recentadvancesand pages 1-2) - Thyroid papillary carcinoma: 1–2% (kyriakidis2023updatedperspectiveson pages 1-2) - Medulloblastoma and hepatoblastoma: ~1–2% each (kyriakidis2023updatedperspectiveson pages 1-2) - Osteomas: 20% (kyriakidis2023updatedperspectiveson pages 1-2) - Dental and osseous anomalies can precede intestinal polyposis; a 2024 review emphasizes early-detection relevance for dentistry. (buki2024raregermlinevariants pages 1-2)

Suggested HPO terms (examples): - Desmoid tumor: Desmoid tumor (HP term availability depends on version) - CHRPE: Congenital hypertrophy of retinal pigment epithelium (HP:0007754) - Osteoma: Osteoma (HP:0011007) - Supernumerary teeth: Supernumerary teeth (HP:0011060)

3.4 Quality-of-life impact

• A systematic review/meta-analysis of NSAID chemoprevention emphasizes that prophylactic colectomy/proctocolectomy is standard but has “major quality-of-life impacts.” (farooq2023nonsteroidalantiinflammatorydrugs pages 1-2)
• Real-world, post-surgical surveillance compliance and QoL measurement is reported in a 2024 institutional study (Saudi Arabia) using SF-36 and EORTC instruments; mean SF-36 domain scores were >60, but surveillance adherence was poor for multiple modalities. (OpenTargets Search: familial adenomatous polyposis)

4. Genetic / Molecular Information

4.1 Causal gene(s)

• APC (HGNC symbol: APC) is the principal causal gene for classic FAP. (buki2024raregermlinevariants pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)

OpenTargets disease–target association: APC is strongly associated with classic FAP and FAP in OpenTargets. (OpenTargets Search: familial adenomatous polyposis)

4.2 Pathogenic variants and classes (high-level)

• Typical pathogenic mechanism is loss of function (truncating/frameshift/nonsense/splice/large deletions). (buki2024raregermlinevariants pages 1-2)
• One review reports de novo mutations ~25% and large deletions ~15% (for APC-associated disease spectrum). (buki2024raregermlinevariants pages 1-2)

Variant class suggestions (for knowledge base): - Nonsense_variant (SO:0001587) - Frameshift_variant (SO:0001589) - Splice_donor/acceptor_variant (SO:0001575/0001574) - Structural variants (deletions/duplications) - Mosaic APC variants (post-zygotic)

4.3 Modifier genes / genetic heterogeneity

Clinical polyposis can be APC-negative and due to other genes; a 2023 review of APC-mutation–negative colorectal adenomatous polyposis highlights recessive contributors (e.g., MUTYH, NTHL1, MMR genes) and dominant contributors (POLE/POLD1, AXIN2). (zhu2023; retrieved but not used as core classic FAP evidence)

For classic FAP specifically, mosaicism and structural variants are important to consider when standard testing is negative. (kyriakidis2023updatedperspectiveson pages 2-4)

4.4 Epigenetics / chromosomal abnormalities

No disease-specific epigenetic signature for classic FAP was directly supported by the retrieved excerpts; however, APC loss leads to downstream transcriptional program changes via Wnt/β-catenin signaling. (kyriakidis2023updatedperspectiveson pages 1-2)

5. Environmental Information

Classic FAP is primarily genetic; however, important non-genetic contributors include: - Trauma/surgery as a risk factor for desmoid tumors in APC pathogenic variant carriers. (kumamoto2023recentadvancesand pages 1-2) - Estrogen exposure as a risk factor for desmoids (suggesting sex-hormone modulation of phenotype). (kumamoto2023recentadvancesand pages 1-2)

No specific infectious agents were supported as triggers in the retrieved excerpts.

6. Mechanism / Pathophysiology

6.1 Core molecular pathway (APC → Wnt/β-catenin dysregulation)

APC functions as a tumor suppressor regulating β-catenin and Wnt signaling; loss-of-function germline variants predispose intestinal epithelial cells to adenoma initiation, with subsequent somatic events driving adenoma–carcinoma progression. (kyriakidis2023updatedperspectiveson pages 1-2)

A review also frames FAP tumorigenesis as a multistep process, noting that carcinogenesis “typically follows APC mutation then KRAS and TP53 mutations.” (kyriakidis2023updatedperspectiveson pages 2-4)

6.2 Causal chain (conceptual)

1) Germline APC loss-of-function (one allele) establishes susceptibility in intestinal stem/crypt compartments. (kyriakidis2023updatedperspectiveson pages 1-2) 2) Second hit in APC (somatic) leads to β-catenin accumulation and transcriptional activation of proliferative programs (adenoma initiation). (kyriakidis2023updatedperspectiveson pages 1-2, kumamoto2023recentadvancesand pages 1-2) 3) Progression occurs with additional pathway alterations (e.g., KRAS/TP53), increasing dysplasia and malignant potential. (kyriakidis2023updatedperspectiveson pages 2-4) 4) Organ-specific extracolonic disease arises via tissue-context effects (e.g., desmoid fibroproliferation; upper GI adenomas). (kumamoto2023recentadvancesand pages 1-2, karstensen2024endoscopicindicatorsin pages 1-2)

6.3 Cellular processes and cell types

Suggested GO biological process terms (examples): - Wnt signaling pathway (GO:0016055) - Regulation of cell proliferation (GO:0042127) - Epithelial cell proliferation (GO:0050673)

Suggested Cell Ontology (CL) terms (examples): - Intestinal epithelial cell (CL:0000066) - Intestinal stem cell (CL term depends on ontology version) - Fibroblast (for desmoid tumors; CL:0000057)

7. Anatomical Structures Affected

7.1 Organ level

• Colon and rectum (primary; colorectal adenomatous polyposis). (karstensen2024endoscopicindicatorsin pages 1-2, kyriakidis2023updatedperspectiveson pages 1-2)
• Duodenum (major post-colectomy cancer morbidity; high prevalence of duodenal adenomas). (karstensen2024endoscopicindicatorsin pages 1-2)
• Stomach (fundic gland polyposis and gastric adenomas/cancer are an area of increasing concern; targeted endoscopic strategies proposed). (aelvoet2023personalizedendoscopicsurveillance pages 2-3, aelvoet2023personalizedendoscopicsurveillance pages 3-5)
• Mesentery/abdomen (desmoid tumors). (kumamoto2023recentadvancesand pages 1-2)
• Thyroid (papillary carcinoma risk). (kyriakidis2023updatedperspectiveson pages 1-2)
• Adrenal glands (increased adrenal mass prevalence in APC-pathogenic cohorts). (lin2024adrenaltumoursin pages 1-2)

Suggested UBERON terms (examples): - Colon (UBERON:0001155) - Rectum (UBERON:0001052) - Duodenum (UBERON:0002114) - Stomach (UBERON:0000945) - Thyroid gland (UBERON:0002046) - Adrenal gland (UBERON:0002369)

7.2 Subcellular level

APC/β-catenin signaling involves cytoplasmic and nuclear β-catenin dynamics (conceptually supported by Wnt pathway role). (kyriakidis2023updatedperspectiveson pages 1-2)

8. Temporal Development

• Onset: polyps typically develop in adolescence; classic FAP features “hundreds to thousands of colorectal adenomatous polyps” from adolescence. (kyriakidis2023updatedperspectiveson pages 1-2)
• Progression: Without prophylactic surgery, CRC risk approaches certainty by age ~50 in classic FAP (review statement). (kyriakidis2023updatedperspectiveson pages 1-2)
• Upper GI progression: A Japanese retrospective cohort study showed marked worsening over time for duodenal adenomas, with stage progression in 71% and strong increases in HGD/large polyps/Spigelman IV over follow-up; endoscopic intervention prevented invasive cancer during observation. (nakahira2023; retrieved but not extracted as evidence ID here)

9. Inheritance and Population

9.1 Inheritance

• Autosomal dominant inheritance is consistently described across reviews and cohorts. (kyriakidis2023updatedperspectiveson pages 1-2, lin2024adrenaltumoursin pages 1-2)

9.2 Epidemiology

Recent sources report broadly concordant estimates: - Prevalence: 2.29–3.2 per 100,000 (review). (kyriakidis2023updatedperspectiveson pages 1-2) - Prevalence: ~1 in 8,000–18,000 (review). (buki2024raregermlinevariants pages 1-2) - Incidence: 1 in 8,300 births (cited UK study within adrenal cohort paper). (lin2024adrenaltumoursin pages 1-2)

9.3 Penetrance/expressivity and mosaicism

• Phenotypic spectrum exists (classic vs attenuated; extracolonic manifestations). (kyriakidis2023updatedperspectiveson pages 1-2, buki2024raregermlinevariants pages 1-2)
• Mosaicism and structural variants can explain previously “unknown etiology” polyposis families; WGS and mosaic screening improved detection in a nationwide registry setting. (kyriakidis2023updatedperspectiveson pages 2-4)

10. Diagnostics

10.1 Clinical criteria

• Classic clinical threshold: >100 colorectal adenomas is repeatedly used to define classic FAP clinically. (karstensen2024endoscopicindicatorsin pages 1-2, lin2024adrenaltumoursin pages 1-2)

10.2 Endoscopic evaluation and staging

• Upper GI disease is commonly staged with Spigelman, but limitations are highlighted: “Spigelman stage IV is an imperfect predictor for duodenal cancer and poor predictor for ampullary cancer,” and modern endoscopy may inflate stage without corresponding risk. (aelvoet2023personalizedendoscopicsurveillance pages 1-2)

10.3 Genetic testing strategy (current practice direction)

A 2023 review summarizes practical recommendations: - If the familial APC pathogenic/likely pathogenic variant is known, targeted single-site testing is appropriate. - If no familial variant is known, multi-gene panels are preferred; consider evaluation for mosaicism using tissues beyond blood (e.g., polyps). (kyriakidis2023updatedperspectiveson pages 2-4)

10.4 Differential diagnosis

The diagnostic differential for adenomatous polyposis includes APC-associated classic/attenuated FAP and other hereditary polyposis syndromes (e.g., MUTYH-associated polyposis, polymerase proofreading-associated polyposis). While not fully enumerated in the classic-FAP excerpts, this heterogeneity is emphasized in clinical genetics discussions and OpenTargets associations. (OpenTargets Search: familial adenomatous polyposis, kyriakidis2023updatedperspectiveson pages 2-4)

11. Outcome / Prognosis

11.1 Cancer risks (selected quantitative estimates)

A 2023 review provides quantitative extracolonic cancer risks and frequencies: - Duodenal cancer described as a leading post-colectomy cause of death; reported “cumulative risk ~4.5% at 57 and 18% at 75.” (kyriakidis2023updatedperspectiveson pages 1-2) - Thyroid papillary carcinoma frequency 1–2%. (kyriakidis2023updatedperspectiveson pages 1-2)

11.2 Desmoid tumors as a major morbidity/mortality driver

A 2023 desmoid-focused review states desmoid tumor is “a major complication that occurs in approximately 10%–25% of familial adenomatous polyposis (FAP) patients” and notes it has been considered “the leading cause of death in patients undergoing colectomy.” (kumamoto2023recentadvancesand pages 1-2)

11.3 Upper GI outcomes (registry data)

In a nationwide cohort (Denmark), 3.4% developed duodenal adenocarcinoma and nearly half of those were advanced at diagnosis, reinforcing the importance of structured surveillance and effective endoscopic intervention pathways. (karstensen2024endoscopicindicatorsin pages 1-2)

12. Treatment

12.1 Surgical and interventional management (real-world implementation)

• Risk-reducing colorectal surgery: A 2023 review notes “the gold-standard treatment to reduce this risk is prophylactic colectomy, typically by the age of 40.” (kyriakidis2023updatedperspectiveson pages 1-2)
• Persistent extracolonic risk: colectomy “constitutes an ineffective way at preventing extra-colonic disease manifestations” such as desmoids/thyroid/duodenal polyposis. (kyriakidis2023updatedperspectiveson pages 1-2)

Suggested MAXO terms (examples): - Colectomy (MAXO term; label depends on MAXO version) - Proctocolectomy - Endoscopic polypectomy - Endoscopic mucosal resection (EMR)

12.2 Endoscopic surveillance and endoscopic therapy protocols (European FAP Consortium, 2023)

A consensus-based strategy proposes personalized surveillance intervals and explicit thresholds for endoscopic resection across the GI tract: - Existing guidelines commonly recommend “1-, 2- or 3-yearly endoscopic surveillance of the rectum and pouch with polypectomy of adenomas >5 mm.” (aelvoet2023personalizedendoscopicsurveillance pages 2-3) - The European FAP Consortium strategy defines personalized intervals “from 3–6 months up to 2 years,” driven by dysplasia grade, resection completeness, and residual adenoma burden. (aelvoet2023personalizedendoscopicsurveillance pages 2-3) - Upper-GI intervention thresholds include duodenal adenoma ≥10 mm, gastric adenoma ≥5 mm, ampullary adenoma ≥10 mm or rapidly progressive, and optical suspicion of high-grade dysplasia; in heavy-burden duodenal disease, polypectomy for ≥5 mm lesions may be considered. (aelvoet2023personalizedendoscopicsurveillance pages 3-5)

Visual evidence (flowcharts): The retrieved figures show the proposed lower- and upper-GI surveillance algorithms and thresholds. (aelvoet2023personalizedendoscopicsurveillance media a5ca449c, aelvoet2023personalizedendoscopicsurveillance media 73b6a57e)

12.3 Pharmacotherapy / chemoprevention

NSAIDs (systematic review/meta-analysis; 2023)

A 2023 meta-analysis of 8 RCTs (279 patients) reported that NSAID therapy (mean ~6.4 months) reduced: - polyp number by 17.4% (95% CI 26.41% to 8.29%; low certainty) - polyp size by 15.9% (95% CI 24.98% to 6.73%; very low certainty) with GI adverse events including stomatitis, diarrhea, and abdominal pain. (farooq2023nonsteroidalantiinflammatorydrugs pages 1-2)

EGFR inhibition (erlotinib) for duodenal polyposis (Gut, 2023)

A Phase II trial of weekly erlotinib (350 mg once weekly for 6 months) reported: - mean duodenal polyp burden change −29.6% (95% CI −39.6% to −19.7%; p<0.0001) - Spigelman downstaging in 12% - grade 2–3 adverse events in 71.7%; most common was acneiform rash (56.5%) - trial registration NCT02961374 (samadder2023phaseiitrial pages 1-2, samadder2023phaseiitrial pages 4-5)

Direct abstract-supported quotes include: “Duodenal polyp burden was significantly reduced after 6 months… with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; p<0.0001)” and “Grade 2 or 3 AEs were reported in 71.7% of subjects.” (samadder2023phaseiitrial pages 1-2)

Eflornithine + sulindac (NEJM, 2020; Phase III)

A Phase III RCT (cited in ClinicalTrials.gov record NCT01483144) found disease progression was not significantly lower with combination therapy versus monotherapy; the registry record explicitly ties NCT01483144 to the NEJM paper (PMID listed in OpenTargets evidence as 32905675). (NCT01483144 chunk 2, OpenTargets Search: familial adenomatous polyposis)

Ongoing / recent trial activity (example)

A recruiting Phase III study is listed for “celecoxib and metformin” in FAP (NCT06545526). (clinical trial registry record retrieved; evidence details not fully extracted from chunks in this run) (OpenTargets Search: familial adenomatous polyposis)

12.4 Expert opinion / analysis (authoritative sources)

• A 2023 review concludes that despite many tested agents, “there has not yet been a chemoprevention agent” that meets desired criteria for long-term safety and clinically meaningful durable effect. (kyriakidis2023updatedperspectiveson pages 1-2)
• An international practice survey shows heterogeneous real-world chemoprevention adoption: “Sixty-nine percent… offer chemoprevention for FAP,” with sulindac and aspirin commonly selected, but substantial variability across experts. (mraz2023; retrieved but not evidence-extracted here)

13. Prevention

13.1 Primary/secondary/tertiary prevention in classic FAP

• Secondary prevention is central: early identification of at-risk relatives (cascade testing) and initiation of colonoscopic surveillance in adolescence/early adulthood is emphasized in reviews; one review notes pediatric at-risk testing/surveillance typically begins at age 10–15. (kyriakidis2023updatedperspectiveson pages 2-4)
• Tertiary prevention includes prophylactic colorectal surgery plus lifelong surveillance of retained rectum/pouch and upper-GI organs, because surgery does not eliminate extracolonic risk. (kyriakidis2023updatedperspectiveson pages 1-2)

13.2 Surveillance as prevention (European FAP Consortium)

The European FAP Consortium provides a prevention-oriented surveillance and intervention framework (individualized intervals 3–6 months to 2 years; explicit size thresholds for resections), intended to reduce cancer incidence while limiting unnecessary surgery. (aelvoet2023personalizedendoscopicsurveillance pages 2-3, aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance media a5ca449c, aelvoet2023personalizedendoscopicsurveillance media 73b6a57e)

14. Other Species / Natural Disease

The retrieved evidence in this run did not include naturally occurring veterinary FAP analogs (OMIA/VetCompass) or explicit cross-species natural disease reports.

15. Model Organisms

The weekly-erlotinib trial paper references preclinical ApcMin/+ mouse evidence (e.g., “greater than 85% decrease” in microadenoma progression in ApcMin/+ mice), indicating ongoing reliance on classic APC-driven mouse models for chemoprevention and mechanistic studies. (samadder2023phaseiitrial pages 5-6)

Commonly used model systems (supported at least at mention level in retrieved evidence): - ApcMin/+ mouse for intestinal adenoma biology and preclinical chemoprevention. (samadder2023phaseiitrial pages 5-6)

(Additional detailed model-organism characterization—organoids, conditional Apc alleles, limitations—was not captured in the extracted evidence set of this run.)

Recent Developments (2023–2024 emphasis): synthesis

1) Shift toward personalized endoscopic management: The European FAP Consortium proposed explicit polypectomy thresholds and individualized surveillance intervals (3–6 months to 2 years), addressing limitations of guideline vagueness and Spigelman staging. (aelvoet2023personalizedendoscopicsurveillance pages 2-3, aelvoet2023personalizedendoscopicsurveillance pages 3-5, aelvoet2023personalizedendoscopicsurveillance media a5ca449c, aelvoet2023personalizedendoscopicsurveillance media 73b6a57e)

2) Duodenal disease burden quantified in national registers: In Denmark, 59.2% of scoped patients had duodenal adenomas; 3.4% developed duodenal adenocarcinoma, with 47% advanced at diagnosis, highlighting ongoing unmet needs in upper-GI surveillance and intervention. (karstensen2024endoscopicindicatorsin pages 1-2)

3) Chemoprevention evidence remains mixed: - NSAIDs show modest reductions in polyp number/size in meta-analysis, with low/very-low certainty and heterogeneity. (farooq2023nonsteroidalantiinflammatorydrugs pages 1-2) - Targeted EGFR inhibition (weekly erlotinib) demonstrated a ~30% reduction in duodenal polyp burden but with frequent (mostly grade 2) adverse events. (samadder2023phaseiitrial pages 1-2, samadder2023phaseiitrial pages 4-5)

4) Extracolonic phenotype expansion in contemporary cohorts: Increased recognition of adrenal masses in APC-pathogenic cohorts (26.7% prevalence in one series) underscores broader surveillance considerations beyond classic organs. (lin2024adrenaltumoursin pages 1-2)

URLs and publication dates (key sources used)

• OpenTargets (disease–target associations; includes MONDO/Orphanet IDs): https://platform.opentargets.org/ (platform snapshot in evidence context) (OpenTargets Search: familial adenomatous polyposis)
• Kyriakidis et al. “Updated Perspectives…” (Aug 2023): https://doi.org/10.2147/TACG.S372241 (kyriakidis2023updatedperspectiveson pages 1-2)
• Aelvoet et al. European FAP Consortium strategy (Jan 2023): https://doi.org/10.1055/a-2011-1933 (aelvoet2023personalizedendoscopicsurveillance pages 1-2)
• Samadder et al. weekly erlotinib Phase II (May 2023): https://doi.org/10.1136/gutjnl-2021-326532 (samadder2023phaseiitrial pages 1-2)
• Karstensen et al. Danish cohort duodenal indicators (Jul 2024): https://doi.org/10.1007/s10689-024-00415-x (karstensen2024endoscopicindicatorsin pages 1-2)
• Büki et al. APC variants and dental/osseous anomalies (Jul 2024): https://doi.org/10.3390/ijms25158189 (buki2024raregermlinevariants pages 1-2)
• Lin et al. Adrenal tumors in APC carriers (Sep 2024): https://doi.org/10.1186/s13053-024-00289-1 (lin2024adrenaltumoursin pages 1-2)
• Farooq et al. NSAID chemoprevention meta-analysis (Jun 2023): https://doi.org/10.1016/j.gastha.2023.05.009 (farooq2023nonsteroidalantiinflammatorydrugs pages 1-2)

Appendix: Trial identifiers mentioned

• NCT02961374 (weekly erlotinib Phase II; Gut 2023) (samadder2023phaseiitrial pages 1-2)
• NCT01483144 (eflornithine + sulindac Phase III; ClinicalTrials.gov record) (NCT01483144 chunk 2)

Included visual evidence

• European FAP Consortium flowcharts (lower GI and upper GI surveillance/thresholds): (aelvoet2023personalizedendoscopicsurveillance media a5ca449c, aelvoet2023personalizedendoscopicsurveillance media 73b6a57e)

References

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