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.

Topics covered

• Germline genes behind pancreatic cancer
• The absolute-risk surveillance threshold
• Which carriers qualify on gene alone
• Surveillance starting ages and modality
• PRSS1 hereditary pancreatitis
• Synthetic lethality, platinum, and PARP inhibitors
• Multi-organ coordination and cascade testing
• Risk-reducing surgery and reproductive counseling
• GINA limits and variants of uncertain significance

Key decisions

• Gate pancreatic surveillance on absolute lifetime risk above approximately five percent, above which cancer detection outweighs the false positives, procedural complications, and cyst-driven anxiety below it.
• Enroll STK11, CDKN2A, PRSS1, and familial pancreatic cancer kindreds on genotype or pedigree alone, but enroll BRCA1, BRCA2, ATM, PALB2, and Lynch carriers only with a first-degree or second-degree relative with pancreatic cancer.
• Start surveillance at thirty to thirty-five for STK11, forty for CDKN2A and PRSS1, and fifty for BRCA, ATM, PALB2, and Lynch, or ten years before the earliest family pancreatic cancer, whichever is younger.
• Alternate annual EUS and pancreatic-protocol MRI with MRCP because they are complementary, EUS for solid lesions and same-session sampling, MRI for cysts and ductal anatomy without procedural risk.
• Offer maintenance olaparib after at least sixteen weeks of platinum-based chemotherapy without progression in germline BRCA metastatic pancreatic cancer, because it roughly doubled progression-free survival and germline panel testing is now standard at diagnosis.
• Do not act on a variant of uncertain significance: it does not justify cascade testing or gene-specific surveillance, and the program stays anchored to personal and family history.
• Counsel carriers that GINA covers health insurance and employment but not life, disability, or long-term care insurance, and advise obtaining those policies before testing.

Study the full chapter on Board Pearls, with practice questions, tables and primary-guideline references: Hereditary GI Cancer Syndromes

Read this episode: boardpearls.com/gi/episodes/hereditary-gi-cancer-syndromes-ep5

Questions or feedback: hello@boardpearls.com.

• (00:00) - Germline genes behind pancreatic cancer
• (00:39) - Two mechanistic gene families
• (01:42) - The absolute-risk surveillance threshold
• (03:50) - Starting ages and surveillance modality
• (04:36) - Alternating EUS and MRI
• (05:51) - PRSS1 hereditary pancreatitis
• (07:03) - Synthetic lethality and PARP inhibitors
• (09:56) - Multi-organ coordination and cascade testing
• (12:53) - GINA limits and the VUS trap

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.

Topics covered

• 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
• Hereditary diffuse gastric cancer and CDH1
• Prophylactic total gastrectomy
• The Cambridge surveillance protocol
• GAPPS as the HDGC differential

Key decisions

• Resect any Peutz-Jeghers small bowel polyp greater than one centimeter, any symptomatic polyp regardless of size, and any polyp showing rapid growth, because growth velocity predicts intussusception better than absolute size.
• Start Peutz-Jeghers surveillance young with baseline EGD and colonoscopy at age eight to ten plus small bowel capsule or MR enterography, avoiding CT enterography because of cumulative radiation across decades.
• Enroll STK11 carriers in pancreatic surveillance on the gene alone, unlike BRCA, ATM, PALB2, and Lynch, because STK11 lifetime pancreatic risk clears the absolute-risk threshold without a family-history modifier.
• Read Cowden as a breast and thyroid syndrome, with annual thyroid ultrasound from diagnosis, breast MRI and mammography from the early thirties, and no prophylactic thyroidectomy because the cancers are follicular and papillary rather than medullary.
• Recommend prophylactic total gastrectomy with Roux-en-Y reconstruction between ages twenty and thirty for confirmed CDH1 carriers, because random biopsy misses multifocal submucosal signet-ring foci that sit beneath grossly intact mucosa.
• Offer the Cambridge protocol of annual EGD with thirty to fifty random biopsies only as a fallback for CDH1 carriers awaiting or declining surgery, counseling explicitly that surveillance failure is documented despite rigorous adherence.
• Add annual breast MRI plus mammography from age thirty for female CDH1 carriers, because lobular breast cancer risk reaches forty to fifty-five percent and mammography detects it less reliably.

Study the full chapter on Board Pearls, with practice questions, tables and primary-guideline references: Hereditary GI Cancer Syndromes

Read this episode: boardpearls.com/gi/episodes/hereditary-gi-cancer-syndromes-ep4

Questions or feedback: hello@boardpearls.com.

• (00:00) - Peutz-Jeghers, STK11, and buccal pigmentation
• (02:05) - Arborizing hamartomas and intussusception
• (03:03) - The small bowel resection threshold
• (04:36) - Multi-organ cancer surveillance
• (05:33) - The recognition cancers to memorize
• (06:57) - The PTEN spectrum and Cowden
• (10:56) - CDH1 and hereditary diffuse gastric cancer
• (13:00) - The Cambridge surveillance fallback
• (14:56) - GAPPS as the differential

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.

Topics covered

• 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

Key decisions

• Start annual colonoscopy at puberty, age ten to twelve, in classic FAP, and delay attenuated FAP and MUTYH-associated polyposis to age twenty to twenty-five because the polyps and cancer arise later.
• Move to prophylactic colectomy for polyps larger than ten millimeters, high-grade dysplasia, rising polyp number, burden too high to clear endoscopically, or symptoms.
• Let the rectum decide the operation: total proctocolectomy with ileal pouch-anal anastomosis when the rectum carries burden, total colectomy with ileorectal anastomosis with annual rectal surveillance when it can be cleared.
• Test for biallelic MUTYH in a patient with multiple adenomas who is APC-negative, especially when a sibling is affected and the parents are not, because the pattern is autosomal recessive.
• Stage the duodenum by Spigelman and set the interval to the stage: EGD every four years at stage zero down to every year at stage three, with side-viewing ampulla inspection each time, because stage four carries a fourteen to thirty-six percent cancer risk and triggers surgical evaluation.
• Treat sulindac and celecoxib as adjuncts only, since they reduce polyp number but do not prevent colorectal cancer or remove the need for surgery.

Study the full chapter on Board Pearls, with practice questions, tables and primary-guideline references: Hereditary GI Cancer Syndromes

Read this episode: boardpearls.com/gi/episodes/hereditary-gi-cancer-syndromes-ep3

Questions or feedback: hello@boardpearls.com.

• (00:00) - Gene sets count, histology, and surgery
• (00:53) - Classic FAP and APC on Wnt signaling
• (01:39) - Attenuated FAP and the Ashkenazi variant
• (02:19) - MUTYH-associated polyposis and recessive inheritance
• (03:30) - Extracolonic stigmata and desmoids
• (04:52) - Colectomy and the rectal decision
• (06:00) - Spigelman-staged duodenal surveillance
• (07:20) - Chemoprevention as adjunct not substitute