Hereditary GI Cancer Syndromes: Hereditary GI Cancer Syndromes: CDH1 and BRCA2

0:00Welcome to Board Pearls. This is episode five of five of the Hereditary GI Cancer Syndromes chapter, in the Special Populations and Acute or Supportive Care module. This episode is hereditary diffuse gastric cancer and hereditary pancreatic cancer, two cancers that are especially hard to find early. The first patient is a young woman who carries her family's CDH1 variant. Her case shows why endoscopy can't find the cancer she's at risk of, why the answer is removing a healthy stomach and when, and what she needs for her breasts. The second patient is a man with a BRCA2 variant whose father died of pancreatic cancer. His case shows who qualifies for pancreatic surveillance and why some genes qualify alone while others need an affected relative, which test is used and from what age, and why every pancreatic cancer gets germline testing.

0:52Here's the first patient. A twenty-six-year-old woman's mother had lobular breast cancer at forty-six, and her maternal uncle died of diffuse gastric cancer at thirty-eight. Her mother tested positive for a pathogenic CDH1 variant, and through cascade testing, so has she. She feels well. Her upper endoscopy, done last month, looked entirely normal.

1:13She has hereditary diffuse gastric cancer syndrome, and she doesn't have cancer yet. The syndrome is autosomal dominant. CDH1, the E-cadherin gene on chromosome 16q22, is the mutated gene in about thirty to fifty percent of clinically defined cases, and CTNNA1, which encodes alpha-E-catenin, E-cadherin's binding partner, accounts for a smaller subset. E-cadherin holds gastric epithelial cells together. When it's lost, poorly cohesive signet-ring cells infiltrate the gastric wall without forming glands, which is the diffuse-type adenocarcinoma the syndrome is named for.

1:50Her family history is the classic pattern that leads to testing. The International Gastric Cancer Linkage Consortium criteria offer germline testing for any of the following: two or more gastric cancers in a family with at least one diffuse, at any age; one diffuse gastric cancer before forty, or before thirty-five in some centers; diffuse gastric cancer and lobular breast cancer in one person or one family, with one diagnosis before fifty; bilateral lobular breast cancer before seventy; early-onset signet-ring cell gastric cancer in any patient; or in situ signet-ring cell carcinoma on a biopsy. CDH1 is also now included on most multi-gene cancer panels, whatever the pre-test probability.

2:31Her uncle's diffuse gastric cancer at thirty-eight meets the age criterion, and his cancer together with her mother's lobular breast cancer before fifty meets the combined criterion. Diffuse gastric cancer and lobular breast cancer in the same family is the signature of CDH1.

2:47Her normal endoscopy doesn't lower her risk, and the reason lies in the kind of cancer she's at risk of. Gastric adenocarcinoma comes in two types under the Lauren classification. Intestinal-type cancer forms glands, rises with age, and often arises from atrophic gastritis with intestinal metaplasia. Diffuse-type cancer is made of poorly cohesive signet-ring cells that infiltrate without forming glands, and it appears at a younger age with a worse prognosis. Hereditary diffuse gastric cancer is the prototypical diffuse tumor.

3:20In CDH1 carriers, the signet-ring cells develop deep beneath intact-looking mucosa, as multifocal microscopic disease that can't be seen on white-light endoscopy until it's advanced. Standard biopsies sample the surface epithelium and miss it, and even meticulous random biopsy at a high count misses some cases. So endoscopic surveillance can't be relied on to find early diffuse cancer in a carrier like her, and her clean scope last month tells her very little.

3:48Because surveillance fails, her recommended management is surgical. Prophylactic total gastrectomy with Roux-en-Y reconstruction is recommended for confirmed CDH1 carriers, typically between the ages of twenty and thirty. It comes after multidisciplinary counseling about what living without a stomach means: lifelong vitamin B12 and iron supplementation, the risk of dumping, weight loss, and a different way of eating.

4:12The evidence that the operation is needed comes from the removed stomachs themselves. When prophylactic gastrectomy specimens are sectioned serially in their entirety, most contain foci of intramucosal signet-ring cell carcinoma, even when the endoscopy before surgery was unremarkable. The cancer was already there while surveillance couldn't see it.

4:32At twenty-six, she's inside the recommended window, so she's offered prophylactic total gastrectomy after counseling, with the timing weighed against her life plans, and with lifelong B12 and iron afterward.

4:44If she declines surgery or wants to delay it, the fallback is annual upper endoscopy under the Cambridge protocol, with many random biopsies, at least thirty to fifty, taken from every gastric region: the antrum, body, fundus, cardia, and transitional zones. It isn't a substitute for surgery, and she's told that early disease has been missed even with rigorous adherence to the protocol. The median age at gastric cancer diagnosis in carriers under surveillance is about thirty-eight, which is why the decision can't be put off for long. If she wants to wait two years for personal reasons, she has a Cambridge protocol endoscopy each year until her operation, with the clear warning that a clean result isn't a guarantee.

5:27Her variant also threatens her breasts. Female CDH1 carriers have a lifetime risk of lobular breast cancer of about thirty-nine to fifty-five percent. Lobular cancer grows with a diffuse architecture that mammography detects less reliably, so her program is annual breast magnetic resonance imaging, MRI, plus mammography starting at thirty, with risk-reducing bilateral mastectomy offered as an option after counseling. Her imaging starts in four years. CTNNA1 carriers receive similar counseling, although their gastric cancer risk is lower and the link to breast cancer is less well established.

6:02Her diagnosis rests on her gene result, and one other inherited gastric syndrome would look different at endoscopy. Gastric adenocarcinoma and proximal polyposis of the stomach, GAPPS, is a separate autosomal dominant syndrome caused by point mutations in the promoter 1B region of APC. It produces fundic gland polyposis with low-grade and high-grade dysplasia confined to the proximal stomach, without colorectal or duodenal polyps, and it's managed like hereditary diffuse gastric cancer, with prophylactic gastrectomy when dysplasia progresses. The three syndromes are told apart by where the disease sits. GAPPS is polyposis of the proximal stomach only. Hereditary diffuse gastric cancer is multifocal disease beneath the mucosa without polyps. And familial adenomatous polyposis, FAP, from episode three, brings duodenal and colonic polyps that GAPPS doesn't. Had her scope shown a carpet of dysplastic fundic gland polyps in the proximal stomach with a normal colon, GAPPS would have been the diagnosis.

7:06Now the second patient. A fifty-two-year-old man carries a pathogenic BRCA2 variant, found after his sister's breast cancer. His father died of pancreatic cancer at sixty-eight. He asks whether he should be screened.

7:20His question is whether his risk of pancreatic cancer is high enough to justify surveillance. About ten to fifteen percent of pancreatic ductal adenocarcinoma is linked to an identifiable germline mutation. The genes fall into two groups: DNA repair genes, BRCA1, BRCA2, PALB2, and ATM, which work through homologous recombination; and inherited pancreatic susceptibility genes, CDKN2A, STK11, PRSS1, and the Lynch genes. A familial pancreatic cancer kindred is a family with two or more affected first-degree relatives, whatever gene is or isn't found, and the risk rises steeply with each affected first-degree relative.

8:07Eligibility rests on absolute lifetime risk, not relative risk. Surveillance helps by finding high-grade dysplasia or stage one cancer, and it harms through false-positive workups, complications of endoscopic ultrasound, EUS, and anxiety over indeterminate cysts. The benefit outweighs the harm above an absolute lifetime pancreatic cancer risk of about five percent.

8:30Some genes cross that line on their own: STK11, CDKN2A, and PRSS1. Others don't: BRCA1, BRCA2, ATM, PALB2, and the Lynch genes need a relative with pancreatic cancer to push the risk over it, a first- or second-degree relative for the first four, and a first-degree relative for Lynch. Familial pancreatic cancer kindreds qualify on their family history, and carriers of TP53, the gene of Li-Fraumeni syndrome, are decided individually.

9:09His BRCA2 variant alone wouldn't qualify him, but his father, a first-degree relative, had pancreatic cancer, and that moves him over the line. Enrolling every BRCA2 carrier would expose many people below the threshold to false positives and procedures, so his father's cancer is what makes surveillance worthwhile for him.

9:28His start age follows from his gene and his family. For BRCA1, BRCA2, PALB2, ATM, the Lynch genes, and familial kindreds, surveillance starts at fifty, or ten years before the earliest case in the family. For CDKN2A and PRSS1, it starts at forty, and for STK11, from episode four, at thirty to thirty-five. Ten years before his father's diagnosis would be fifty-eight, which is later than fifty, so fifty applies, and at fifty-two he starts now.

10:04His test is annual EUS or pancreatic-protocol MRI with magnetic resonance cholangiopancreatography, MRCP, and most protocols alternate the two every twelve months because they find different things. EUS detects solid lesions, allows fine-needle aspiration of anything suspicious, and shows changes in the pancreatic tissue. MRI with MRCP is better for following cysts and for showing the ducts, and it avoids the procedural risk of EUS. A new cyst, a solid lesion, or main pancreatic duct dilation leads to EUS-guided sampling and multidisciplinary review, with the finding then managed as chapter twenty-six describes. Surveillance programs have found high-grade dysplasia and stage one cancers in carriers, although whether they improve survival compared with symptomatic detection is still being studied.

10:57Had his variant been in CDKN2A, he'd have qualified on the gene alone, without an affected relative, from forty.

11:05PRSS1, one of the genes that qualifies alone, causes hereditary pancreatitis, and its cancer risk is shaped by something the patient controls. Germline PRSS1 mutations in cationic trypsinogen carry a markedly raised pancreatic cancer risk, a standardized incidence ratio of about fifty-three. Estimates of the absolute risk vary widely, with older series putting it far higher than a contemporary United States cohort, which found a cumulative risk of death from pancreatic cancer of about seven percent by seventy. Smoking amplifies the risk dramatically, so these patients have annual EUS or MRI from forty with smoking cessation counseling at every visit. Prophylactic total pancreatectomy with islet autotransplantation is rare, reserved for PRSS1 patients with a high cumulative cancer risk plus intractable pain, where the damage of chronic pancreatitis and the cancer risk together justify removing the organ. Chapter twenty-six covers hereditary pancreatitis itself.

12:09His father's cancer raises the last point: every patient with pancreatic cancer gets germline testing at diagnosis, because the result changes treatment. Patients with germline BRCA1, BRCA2, or PALB2 mutations and metastatic pancreatic cancer benefit from platinum chemotherapy and from maintenance with a poly adenosine diphosphate-ribose polymerase, PARP, inhibitor, through synthetic lethality.

12:36The mechanism explains the benefit. These genes are needed for homologous recombination, the high-fidelity repair of DNA double-strand breaks. Platinum creates DNA crosslinks that need homologous recombination to repair, so cells without it die. PARP inhibitors block the other repair pathway, the one for single-strand breaks, leaving those cells with neither pathway. In a randomized trial of germline BRCA-mutated metastatic pancreatic cancer that hadn't progressed on first-line platinum, olaparib maintenance roughly doubled progression-free survival, and it's approved by the Food and Drug Administration for that use. Somatic BRCA or PALB2 mutations found on tumor sequencing also predict benefit from platinum, by the same mechanism.

13:22So the germline panel is sent when pancreatic cancer is diagnosed, not later, because the result can decide the first chemotherapy. Had his father been tested at diagnosis, his BRCA2 variant could have guided his treatment, and his family would have learned of it sooner.

13:37Here are the traps the boards set in these patients. Trusting a normal endoscopy in a CDH1 carrier. Offering surveillance instead of gastrectomy as the primary plan. Forgetting lifelong B12 and iron after gastrectomy. Forgetting breast MRI from thirty for lobular breast cancer. Confusing GAPPS with hereditary diffuse gastric cancer or with FAP. Enrolling BRCA or Lynch carriers in pancreatic surveillance without an affected relative. Requiring an affected relative for STK11, CDKN2A, or PRSS1 carriers. Starting pancreatic surveillance at the wrong age. Forgetting smoking cessation in hereditary pancreatitis. And skipping germline testing in a newly diagnosed pancreatic cancer.

14:23So, start to finish. CDH1 carriers are offered prophylactic total gastrectomy, usually in their twenties, because diffuse signet-ring cancer develops beneath normal-looking mucosa where surveillance misses it. Those who decline or delay have yearly endoscopy with thirty or more random biopsies under the Cambridge protocol. Female carriers add breast MRI and mammography from thirty for lobular breast cancer. Proximal fundic gland polyposis with dysplasia and no colonic polyps is GAPPS.

14:52Pancreatic surveillance is offered only above about five percent lifetime risk: to STK11, CDKN2A, and PRSS1 carriers on the gene alone, to BRCA1, BRCA2, PALB2, ATM, and Lynch carriers only with an affected relative, and to familial kindreds. It's yearly EUS or MRI, from fifty or ten years before the youngest family case, and earlier for STK11, CDKN2A, and PRSS1. And every pancreatic cancer gets germline testing at diagnosis, because BRCA and PALB2 carriers benefit from platinum and olaparib.

15:32That completes the Hereditary Gastrointestinal Cancer Syndromes chapter, and the Special Populations and Acute or Supportive Care module.

15:40For 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 five of five of chapter thirty-six, and I'll see you in the next one.