Familial cancer syndromes - familial adenomatous polyposis

Description

Autosomal dominant, APC tumour-suppressor mutation -> hundreds to thousands of colorectal adenomas
Classic FAP: >100 (often >1000) adenomas from teenage years, ~100% progress to CRC untreated
Attenuated FAP (AFAP) - fewer polyps (10-100), later onset, lower/delayed CRC risk

~1 in 10,000-30,000
Accounts for <1% of all CRC (much rarer than Lynch)
Autosomal dominant, ~25% de novo mutations; near-complete penetrance for classic FAP

Germline APC mutation (chr5) -> loss of Wnt pathway regulation -> unrestrained adenoma formation
"Two-hit" model - second (somatic) APC hit triggers each adenoma -> explains multiplicity
Mutation position correlates loosely with phenotype severity (genotype-phenotype correlation) and extracolonic manifestations
MUTYH-associated polyposis (MAP) - autosomal recessive phenocopy, biallelic MUTYH mutations, similar polyposis picture - test if APC negative

Colonoscopy - carpet of adenomas (>100) diagnostic of classic FAP
Germline APC gene testing confirms, enables cascade testing of relatives
Screen relatives from puberty (~age 10-12) with sigmoidoscopy/colonoscopy if familial mutation known or family history strongly suggestive
Upper GI endoscopy from diagnosis - duodenal/ampullary polyps

Definitive

Prophylactic colectomy - once polyp burden becomes unmanageable endoscopically (typically late teens-20s), before cancer develops
- Restorative proctocolectomy with IPAA, or colectomy with IRA depending on rectal polyp burden
Ongoing pouch/rectal remnant surveillance post-surgery - polyps and cancer can still arise

Surveillance while colon intact / after surgery

Colonoscopy - annual from onset of polyps (or from ~10-15yrs if known mutation) until colectomy
Upper GI (duodenum/ampulla) - endoscopic surveillance from ~25-30yrs, interval by Spigelman stage of duodenal polyposis
Desmoid tumours - surveillance/imaging if abdominal symptoms - major cause of morbidity post-colectomy
Thyroid palpation/ultrasound (papillary thyroid cancer risk)

Duodenal/ampullary adenomas -> duodenal cancer - now a leading cause of death after colectomy
Desmoid tumours - especially post-surgery, can cause significant morbidity
Gardner syndrome variant - osteomas, dental abnormalities, epidermoid cysts, desmoids
Turcot syndrome variant - medulloblastoma (with APC mutation; distinct from Lynch-associated glioblastoma)
Papillary thyroid cancer (esp. young women), hepatoblastoma (childhood), congenital hypertrophy of retinal pigment epithelium (CHRPE - clinical marker, not malignant)

CRC is near-universal by 40s-50s without colectomy - prophylactic surgery is standard of care, not optional
Post-colectomy mortality now increasingly driven by duodenal cancer and desmoid disease rather than CRC
AFAP - later CRC onset (~50s), sometimes managed with intensive polypectomy surveillance alone rather than early colectomy
Lifelong surveillance required even after colectomy - extracolonic disease persists

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