Hereditary GI Cancer Syndromes

• Audio chapter
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• ABIM-format MCQs
  5-option vignettes with full wrong-answer teaching.
• Study guide
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What this chapter covers

• Section 36.1: Diagnostic framework for hereditary GI cancer

  Hereditary GI cancer syndromes are inherited cancer predispositions in which germline mutations confer high lifetime risk of GI and extra-GI malignancies, and the diagnostic task in every suspected case is the same regardless of which syndrome the patient ultimately has.

• Section 36.2: Lynch syndrome

  Lynch syndrome is autosomal dominant, caused by germline mutations in mismatch-repair genes MLH1, MSH2, MSH6, PMS2, or by 3' EPCAM deletions that silence MSH2 by promoter methylation.

• Section 36.3: Familial adenomatous polyposis, attenuated FAP, and MUTYH-associated polyposis

  Classic familial adenomatous polyposis is autosomal dominant, caused by germline mutation of the APC tumor suppressor on chromosome 5q21, with 1 in 10,000 incidence and roughly 25 percent of cases arising as de novo mutation in patients without a family history.

• Section 36.4: Peutz-Jeghers syndrome

  Peutz-Jeghers syndrome is autosomal dominant, caused by germline mutation in STK11 (also called LKB1) on chromosome 19p13.3, with detection in approximately 80 percent of clinically defined cases.

• Section 36.5: Cowden syndrome and the PTEN hamartoma tumor syndrome spectrum

  Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) sit in the PTEN hamartoma tumor syndrome (PHTS) spectrum, autosomal dominant, caused by germline mutations in PTEN on chromosome 10q22-23.

• Section 36.6: Hereditary diffuse gastric cancer (CDH1, CTNNA1)

  Hereditary diffuse gastric cancer (HDGC) is autosomal dominant, caused by germline mutations in CDH1 (the E-cadherin gene) on chromosome 16q22 in approximately 30 to 50 percent of clinically defined cases, with CTNNA1 (encoding alpha-E-catenin, the binding partner of E-cadherin) accounting for a smaller subset.

• Section 36.7: Hereditary pancreatic cancer and the CAPS protocol

  Approximately 10 to 15 percent of pancreatic ductal adenocarcinoma is associated with an identifiable germline mutation, and the genes converge on either DNA-repair pathways (homologous recombination through BRCA1, BRCA2, PALB2, and ATM) or inherited pancreatic susceptibility (CDKN2A, STK11, PRSS1, Lynch).

• Section 36.8: Multi-organ coordination, cascade testing, and genetic counseling

  Hereditary GI cancer syndromes require coordinated multi-organ care because no single specialist sees the whole picture, and the dominant practical failure mode is the carrier whose colonoscopy stays on schedule but whose gynecologic, urologic, or dermatologic surveillance has lapsed for years.

Podcast episodes

1. 01

   Diagnostic Framework

   This episode covers the diagnostic framework for hereditary GI cancer: universal MSI and MMR immunohistochemistry on colorectal cancer, the BRAF and MLH1 promoter methylation reflex that separates sporadic from Lynch, the multi-gene panel logic, and the multidisciplinary referral that cascade testing requires.

2. 02

   Lynch Syndrome

   This episode covers Lynch syndrome: the MMR-gene-specific cancer risk that drives gene-specific surveillance intervals, the colorectal and endometrial and urothelial and gastric programs, aspirin chemoprevention, checkpoint inhibition in MSI-high disease, and the Lynch variants.

3. 03

   Adenomatous Polyposis

   This episode covers the adenomatous polyposis syndromes: FAP and attenuated FAP with APC, the Spigelman-staged duodenal surveillance and the timing of colectomy, and MUTYH-associated polyposis with its biallelic recessive pattern.

4. 04

   Hamartomatous and HDGC

   This episode covers the hamartomatous polyposis syndromes and hereditary diffuse gastric cancer: Peutz-Jeghers syndrome with STK11 and its mucocutaneous pigmentation, the PTEN hamartoma spectrum including Cowden, and CDH1-driven hereditary diffuse gastric cancer where prophylactic total gastrectomy is the standard.

5. 05

   Pancreatic and Coordination

   This episode covers hereditary pancreatic cancer and the multi-organ coordination of cascade testing: the CAPS protocol applying EUS and MRI surveillance to BRCA2, PALB2, ATM, CDKN2A, PRSS1, and familial pancreatic cancer kindreds, and the multi-organ coordination of cascade testing and genetic counseling that ties together every hereditary GI cancer...