Hereditary GI Cancer Syndromes

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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

   Hereditary GI Cancer Syndromes: Finding Syndromes

   The organizing idea is that a hereditary cancer syndrome is found by testing tumors, not by relying on pedigree, and that a confirmed diagnosis becomes work for a whole family. The episode begins with universal mismatch repair immunohistochemistry on every colorectal and endometrial cancer. It then shows how the pattern of lost proteins chooses the next test: BRAF and methylation testing for MLH1 and PMS2 loss, germline testing for the other patterns, and EPCAM when MSH2 and MSH6 are lost together. It goes on to panel testing after counseling, coordinated surveillance across organs, cascade testing of first-degree relatives, the limits of GINA, handling a variant of uncertain significance, and risk-reducing surgery.

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2. 02

   Hereditary GI Cancer Syndromes: Lynch Syndrome

   Lynch syndrome is a mismatch repair defect, and every part of a carrier's program follows from what that defect breaks. The episode follows a 24-year-old MSH2 carrier found by cascade testing. It starts with microsatellite instability and why MSI-high tumors respond to checkpoint inhibitors, then shows how each gene sets organ-specific risk. Next come colonoscopy timing and interval, extended colectomy and pembrolizumab, then urinary tract, stomach, pancreas, prostate and skin surveillance. Aspirin and the gynecologic program with risk-reducing surgery follow. The episode ends with Muir-Torre, Turcot, constitutional mismatch repair deficiency, familial colon cancer syndrome X, and the common board traps.

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3. 03

   Hereditary GI Cancer Syndromes: FAP and MUTYH

   The episode is organized around the idea that one gene defect, or one repair defect, can produce hundreds of adenomas, and the care that follows is largely about what happens after the colon is removed. It follows a young woman with classic FAP: how the diagnosis is made, including findings outside the colon, when colonoscopy starts, when colectomy is indicated, and which operation fits her rectum. It then turns to duodenal surveillance by Spigelman stage, desmoid tumors, thyroid ultrasound, and reproductive counseling. A second patient shows how recessive MUTYH polyposis hides in a family, and the episode closes with the common board traps.

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4. 04

   Hereditary GI Cancer Syndromes: Hamartoma Polyps

   This episode covers the two hamartomatous polyposis syndromes through two patients. A young man with an intussusception and buccal pigmentation has Peutz-Jeghers syndrome from STK11. His main danger is obstruction and short bowel rather than cancer, so large or growing small bowel polyps come out and surveillance starts at eight to ten. Cancer surveillance outside the gut follows, with breast, pancreatic, gynecologic, and testicular programs. A woman with macrocephaly, facial papules, diffuse glycogenic acanthosis, and mixed polyps has Cowden syndrome from PTEN. Her main cancers are breast, thyroid, endometrial, and renal, so she enters multi-organ surveillance, with endoscopy from thirty-five.

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5. 05

   Hereditary GI Cancer Syndromes: CDH1 and BRCA2

   Both cancers are hard to find early, so management rests on the gene and the family history rather than on a normal test. A CDH1 carrier is offered prophylactic total gastrectomy in her twenties because diffuse signet-ring cancer grows beneath normal-looking mucosa. Cambridge protocol endoscopy is the fallback, and breast MRI starts at thirty. GAPPS is told apart from hereditary diffuse gastric cancer and FAP by where the disease sits. Pancreatic surveillance is offered above about five percent lifetime risk. Some genes qualify alone and others need an affected relative. The episode then covers start age, test choice, PRSS1, and germline testing for every pancreatic cancer.

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Key topics

• ·Universal tumor screening for Lynch syndrome
• ·Mismatch repair IHC versus microsatellite instability
• ·Protein loss patterns and the next test
• ·BRAF V600E and MLH1 methylation testing
• ·Multigene germline panels and pre-test counseling
• ·Coordinated multi-organ surveillance
• ·Cascade testing of first-degree relatives
• ·GINA coverage and its limits
• ·Variant of uncertain significance
• ·Risk-reducing surgery and reproductive counseling
• ·Mismatch repair and microsatellite instability
• ·Lynch tumor features and pedigree criteria
• ·Gene-specific organ risk
• ·Colonoscopy start age and interval
• ·Extended colectomy and pembrolizumab
• ·Urinary tract and gastric surveillance
• ·Pancreatic, prostate and skin screening
• ·Aspirin chemoprevention
• ·Gynecologic surveillance and hysterectomy
• ·Rare variants and familial colon cancer syndrome X
• ·Classic FAP and APC biology
• ·New mutations and unaffected parents
• ·CHRPE and Gardner syndrome
• ·Attenuated FAP and the I1307K variant
• ·Colonoscopy start ages
• ·Colectomy indications and choice of operation
• ·Spigelman staging of duodenal adenomas
• ·Desmoid tumors after colectomy
• ·Thyroid cancer and reproductive counseling
• ·MUTYH-associated polyposis