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

   Tumor Screening and Reflex Testing

   Episode one of the Hereditary GI Cancer Syndromes chapter builds the diagnostic framework the rest of the series depends on. The organizing idea: universal tumor testing catches the carriers that pedigree gatekeeping misses, because family history alone overlooks thirty to fifty percent of them. The four-protein immunohistochemistry pattern then decides the next move, with combined MLH1 and PMS2 loss running a sporadic-cancer rule-out before germline sequencing and everything else reflexing straight to the blood test. The through-line is that protein-loss pattern drives testing, and once a proband is confirmed, cascade testing of relatives becomes the highest-yield step.

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2. 02

   Specific Risk

   Episode two takes Lynch syndrome, the syndrome the diagnostic framework most often surfaces, and anchors everything to one idea: lifetime cancer risk varies sharply by gene, and that gene-specific risk sets each surveillance interval to the dwell time of preinvasive disease in that organ. MLH1 and MSH2 carriers drive high colorectal and endometrial risk, while MSH6 flips uterine cancer above colorectal and MSH2 concentrates the upper urothelial risk. The reasoning extends to why the colonoscopy interval is short, why the cancer operation is extended, why endometrial surveillance is a bridge to hysterectomy, and why aspirin and pembrolizumab both trace back to the mutational burden the syndrome generates.

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3. 03

   Adenomatous Polyposis: FAP and MUTYH

   Episode three works the adenomatous polyposis syndromes by their governing logic: if you know the gene, you know the polyp count, the polyp type, and the surgery. APC drives classic FAP toward near-certain colorectal cancer by forty, the same gene at its ends produces the softer attenuated phenotype, and biallelic MUTYH mimics attenuated FAP through an autosomal recessive pattern of affected siblings and unaffected parents. The surgical pivot is not whether to take the colon but whether to take the rectum, which decides itself on polyp burden. After the colon is gone the duodenum becomes the surveillance organ, with Spigelman staging turning ampullary adenomas into an EGD interval and a pancreaticoduodenectomy conversation.

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4. 04

   Hamartomatous Polyposis and Diffuse Gastric Cancer

   Episode four moves from adenoma to hamartoma, where the dominant risk shifts away from colorectal cancer. STK11 drives Peutz-Jeghers, and the resection threshold is calibrated to intussusception rather than cancer, so any small bowel polyp over one centimeter comes out. PTEN drives Cowden, where the cancer burden tracks baseline PI3K signaling into breast and thyroid and the GI role is recognition through mixed-histology polyposis. CDH1 flips the algorithm hardest: multifocal submucosal signet-ring disease beneath intact mucosa makes endoscopy unreliable, so prophylactic total gastrectomy between twenty and thirty is the standard of care. The thread is constant, the gene dictates the histology, the histology dictates the natural history, and the natural history dictates whether the answer is surveillance, polyp-by-polyp resection, or removal of the organ.

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5. 05

   Hereditary Pancreatic Cancer and Coordination

   Episode five closes the chapter with hereditary pancreatic cancer and the family-systems coordination that binds every syndrome together. The gating principle is absolute lifetime risk, not relative risk: surveillance begins above roughly five percent, so STK11, CDKN2A, PRSS1, and familial kindreds qualify on genotype alone while BRCA1, BRCA2, ATM, PALB2, and Lynch enter only with a family-history driver. The treatment side ties platinum and PARP inhibitors back to synthetic lethality in homologous-recombination-deficient tumors. The coordination side names the real failure mode, the carrier whose colonoscopy stays on schedule while gynecologic or urologic surveillance lapses, and the board traps around cascade testing, the GINA insurance gap, and the non-actionable variant of uncertain significance.

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Key topics

• ·Why tumor testing replaces pedigree gatekeeping
• ·Universal four-protein MMR immunohistochemistry
• ·Universal endometrial IHC and the sentinel cancer
• ·The reflex pathway and IHC patterns
• ·MLH1 and PMS2 loss with the BRAF and methylation gate
• ·EPCAM and the MSH2 and MSH6 pattern
• ·Multi-gene panels and phenotype overlap
• ·Cascade testing and multidisciplinary referral
• ·Mismatch-repair genetics and the MSI phenotype
• ·Classic Lynch tumor histology and late-presenting carriers
• ·Amsterdam and Bethesda criteria
• ·Gene-specific lifetime cancer risk
• ·Colorectal surveillance and extended colectomy
• ·Endometrial surveillance as a bridge to hysterectomy
• ·Urothelial, gastric, and pancreatic programs
• ·Aspirin chemoprevention and checkpoint inhibition
• ·Lynch variants and Syndrome X
• ·Reasoning from gene to polyp count to surgery
• ·Classic FAP and APC on Wnt signaling
• ·Attenuated FAP and the Ashkenazi variant
• ·MUTYH-associated polyposis and recessive inheritance
• ·FAP extracolonic stigmata and desmoids
• ·Prophylactic colectomy and the rectal decision
• ·Spigelman-staged duodenal surveillance
• ·Chemoprevention as adjunct not substitute
• ·Peutz-Jeghers, STK11, and buccal pigmentation
• ·Arborizing hamartomas and intussusception risk
• ·Small bowel resection thresholds
• ·Peutz-Jeghers multi-organ cancer surveillance
• ·PTEN hamartoma spectrum and Cowden