Hereditary GI Cancer Syndromes: Hereditary GI Cancer Syndromes: Finding Syndromes

0:00Welcome to Board Pearls. This is episode one of five of the Hereditary GI Cancer Syndromes chapter, in the Special Populations and Acute or Supportive Care module. This episode is how a hereditary cancer syndrome is found, and what happens to a family once it is. The first patient is a woman whose endometrial cancer turns out to carry a message for her relatives. Her case shows why every colorectal and endometrial cancer is screened whatever the family history, how the pattern of lost proteins decides the next test, how a germline panel confirms the syndrome, and what follows for her and her family: coordinated surveillance, cascade testing, the limits of the Genetic Information Nondiscrimination Act, GINA, and what to do with a variant of uncertain significance. The second patient is a man whose abnormal tumor stain turns out not to be inherited, and his case shows why one common pattern usually means a sporadic cancer.

0:53Here's the first patient. A forty-seven-year-old woman has just had a hysterectomy for endometrial cancer. She has no family history she knows of, though her father was adopted. Her tumor's mismatch repair immunohistochemistry shows loss of MSH2 and MSH6, with MLH1 and PMS2 retained.

1:12Her tumor's loss of MSH2 and MSH6 points to Lynch syndrome, an inherited defect in DNA mismatch repair, and it was found only because her tumor was stained. Lynch syndrome belongs to the hereditary gastrointestinal, GI, cancer syndromes, inherited predispositions in which a germline mutation confers a high lifetime risk of GI and other cancers. In every suspected case, the work is the same: recognize the cancer pattern in the patient and family, start the right tumor or germline test, and build a surveillance program for every organ at risk.

1:47Her case is the reason tumors are screened rather than families. Selecting patients by pedigree alone misses thirty to fifty percent of carriers, so universal mismatch repair immunohistochemistry, IHC, on every newly diagnosed colorectal and endometrial cancer is the standard of care for Lynch screening, and some institutions extend it to small bowel, urothelial, and gastric tumors. Universal testing of endometrial cancers finds Lynch syndrome in about five percent of new cases that family history would have missed, and a woman whose first cancer is endometrial rather than colorectal is exactly the carrier the pathway was built to catch. Microsatellite instability testing by polymerase chain reaction, PCR, is the alternative, and the two agree closely enough that each institution chooses one. With no known family history and an adopted father, her pedigree could never have flagged her. Her tumor did.

2:44The pattern of lost proteins decides her next test. The commonest abnormal pattern, combined loss of MLH1 and PMS2, doesn't yet mean Lynch syndrome. About seventy percent of colorectal cancers with that pattern are sporadic, caused by a somatic BRAF V600E mutation and hypermethylation of the MLH1 promoter rather than a germline mutation. So MLH1 and PMS2 loss leads first to tumor BRAF V600E testing, then, if that's negative, to MLH1 promoter methylation testing, and only if that's negative too, to germline sequencing.

3:22Her pattern is different. Isolated loss of MSH2, MSH6, or PMS2 has no comparable somatic explanation, so it goes straight to germline testing, without BRAF or methylation testing, which have no meaning for these patterns. Combined loss of MSH2 and MSH6 can also come from EPCAM, because three-prime deletions in EPCAM silence the MSH2 promoter and produce the same staining pattern, and EPCAM-driven Lynch behaves clinically like MSH2-driven Lynch. Chapter thirty covers the BRAF and methylation testing in more detail.

4:01Her germline test is a panel rather than a single gene. Phenotypes overlap, and a patient who looks like one syndrome often carries a mutation in another gene that a panel catches, so single-gene testing has been largely displaced. The panel is chosen by the dominant picture: a GI cancer panel, a polyposis panel, or a comprehensive hereditary cancer panel, depending on whether colorectal cancer, polyposis, or a multi-organ pattern dominates. For her, the panel must include EPCAM as well as MSH2, because her staining pattern could come from either.

4:35Testing begins with counseling. Pre-test counseling covers informed consent, the family history, and what positive, negative, and uncertain results would mean, including the limits of GINA. A three-generation pedigree, with tumor types, ages at diagnosis, and pathology where available, sets the pre-test probability and the testing strategy. The Amsterdam two and revised Bethesda criteria still stratify risk, even though tumor screening and panels have largely replaced them in deciding who's tested, and validated tools help: PREMM5, MMRPro, and MMRPredict for Lynch, BOADICEA for hereditary breast and ovarian cancer, and PennII for Cowden syndrome.

5:17After counseling, her panel shows a pathogenic MSH2 variant, which confirms Lynch syndrome.

5:24Now the second patient. A sixty-eight-year-old man has a right-sided colon cancer, and his tumor shows loss of MLH1 and PMS2.

5:33His pattern is the one that's usually sporadic, so he probably doesn't have Lynch syndrome, and the next test is on his tumor rather than his blood. His tumor is tested for BRAF V600E, and it's positive, which points to a sporadic cancer from MLH1 promoter hypermethylation rather than a germline mutation. Had his BRAF test been negative, his tumor would have been tested for MLH1 promoter methylation, and only if that had also been negative would he have gone to germline testing. His relatives aren't contacted until his tumor tests are complete.

6:06Her confirmed diagnosis changes her care across every organ at risk. A Lynch carrier needs colonoscopy, urinalysis, upper endoscopy, endometrial sampling, transvaginal ultrasound, dermatology review, prostate screening in men, and a discussion of risk-reducing total hysterectomy with bilateral salpingo-oophorectomy. That work spans gastroenterology, gynecology, urology, dermatology, and surgical oncology, and no single specialist sees all of it. The usual failure is a carrier whose colonoscopy stays on schedule while gynecologic, urologic, or dermatologic surveillance lapses for years. Genetic counseling is what holds the program together. Her uterus is already gone, but the rest of her program isn't, so her follow-up plan lists every organ, each with a named owner.

6:57Her result matters most for her family. Cascade testing of first-degree relatives for the specific familial variant is the single highest-yield public health intervention in hereditary cancer prevention, and it changes a family's cancer outcomes more durably than anything done for the first patient alone. One confirmed variant typically identifies several at-risk relatives who would otherwise have been found only after a cancer in the next generation. It's efficient because a known variant turns a search for an unknown gene into a targeted single-site test, which is faster, cheaper, and easier to interpret. So cascade testing is the main task in the months after her result. She has a sister and two adult children, and each is offered single-site testing for her MSH2 variant.

7:41Before her relatives give a sample, they're told what GINA does and doesn't protect. The Genetic Information Nondiscrimination Act protects against discrimination in health insurance and employment based on genetic results. It doesn't cover life insurance, disability insurance, or long-term care insurance, although patients and clinicians often assume it's comprehensive. So cascade counseling routinely advises obtaining life and disability insurance before testing, if a relative doesn't already have it, because a positive result can affect underwriting in those categories. When her son asks whether a positive test could affect him, he's told which protections exist and which don't, before he's tested.

8:22Her sister's own testing raises a different problem. She had a panel elsewhere, and it returned a variant of uncertain significance, a VUS, in a different gene. A VUS isn't actionable. It doesn't justify cascade testing of relatives or gene-specific surveillance beyond what personal and family history would indicate, and it isn't a positive result. Variants are often reclassified over time, most often to benign as population data accumulate, so patients are recontacted periodically for updated interpretation. Telling a relative with a VUS that she has a Lynch mutation and entering her into Lynch surveillance is a common error. Her sister's plan rests on her own history and on single-site testing for the family's MSH2 variant, not on the VUS.

9:06Risk-reducing surgery is planned around fertility, hormones, surgical risk, and the surveillance that continues afterward. In Lynch syndrome, hysterectomy with bilateral salpingo-oophorectomy is offered once childbearing is complete, because in a study of prophylactic surgery, no carrier who had the operation developed endometrial or ovarian cancer. The same planning applies to the operations of the other syndromes in this chapter. Prophylactic total gastrectomy in hereditary diffuse gastric cancer is offered between twenty and thirty. Risk-reducing mastectomy in BRCA1, BRCA2, and CDH1 carriers substantially lowers breast cancer risk. Proctocolectomy in familial adenomatous polyposis, FAP, is timed to polyp burden and dysplasia, typically in the late teens or early twenties. Each operation leaves its own follow-up: annual rectal surveillance after an ileorectal anastomosis in FAP, annual breast surveillance after risk-reducing oophorectomy in Lynch, and lifelong vitamin B12 and iron after total gastrectomy.

10:09Reproductive counseling carries the conversation into the next generation. Pre-implantation genetic testing is available for the autosomal dominant syndromes, including Lynch, FAP, Peutz-Jeghers, Cowden, hereditary diffuse gastric cancer, and hereditary breast and ovarian cancer, letting carrier couples select unaffected embryos during in vitro fertilization. Prenatal diagnosis by chorionic villus sampling or amniocentesis is the alternative once a pregnancy is established. If her daughter tests positive and plans a family, that conversation belongs in her cascade visit, along with when she'll consider her own risk-reducing surgery. Psychological counseling supports young relatives through their testing decisions and through the surveillance fatigue that builds over years.

10:56Here are the traps the boards set in these patients. Relying on family history to decide which tumors are screened. Sending MLH1 and PMS2 loss straight to germline testing. Ordering BRAF or methylation testing for loss of MSH2, MSH6, or isolated PMS2. Forgetting EPCAM when MSH2 and MSH6 are lost together. Ordering a single-gene test when a panel fits. Letting surveillance outside the colon lapse. Skipping cascade testing of first-degree relatives. Assuming GINA covers life or disability insurance. And acting on a variant of uncertain significance.

11:33So, start to finish. Every colorectal and endometrial cancer is screened for mismatch repair loss, by IHC or microsatellite instability, because family history alone misses a third to a half of carriers. Loss of MLH1 and PMS2 needs BRAF V600E and then MLH1 promoter methylation testing before germline testing, because most of those cancers are sporadic. Loss of MSH2, MSH6, or isolated PMS2 goes straight to germline testing, and combined MSH2 and MSH6 loss can mean EPCAM. Germline testing uses a multigene panel after pre-test counseling.

12:16Once a carrier is confirmed, every organ at risk is coordinated, first-degree relatives are tested for the family variant, and they're told that GINA doesn't cover life, disability, or long-term care insurance. Risk-reducing surgery is timed to fertility and risk. And a variant of uncertain significance is never acted on; those patients are managed on their personal and family history.

12:38Episode two is Lynch syndrome.

12:40For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of five of chapter thirty-six, and I'll see you in the next one.