Genetic Disorder Reference Sheet: CDH1 and Hereditary Diffuse Gastric Cancer
Pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), a poorly differentiated adenocarcinoma that infiltrates into the stomach wall. It causes the stomach wall to thicken without forming a distinct mass, which limits effective screening (https://www.ncbi.nlm.nih.gov/books/NBK1139/) strategies.
CDH1 alterations are also associated (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) with increased risk for breast cancer (typically lobular), so patients undergoing genetic counseling may be tested for variants. Genetic counseling and possible testing are recommended (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434) for all patients diagnosed with diffuse gastric cancer.
CDH1 is considered a high-penetrance gene, meaning that its associated risk of leading to one or more malignancies is greatly elevated. Understanding risks, average age of diagnosis, and family history helps clinicians guide screening and prevention recommendations.
- The average age at onset of HDGC is 38 years (range = 14–69 years), with most cancers occurring before age 40.
- The cumulative risk of gastric cancer by age 80 is 70% for men and 56% for women.
- Women also have a 40%–60% risk for lobular breast cancer, with an average age of 53 at onset.
- Colorectal cancer risk may be increased, especially in families with a history of the disease.
Prevention and Early Detection
In families with a known pathogenic variant, testing is generally offered around age 16 because of the risk of early-onset malignancy and the need to start intensive surveillance (https://www.ncbi.nlm.nih.gov/books/NBK1139/) and consider risk-reducing strategies.
Risk-reducing surgery: Individuals with a germline CDH1 pathogenic variant have been found to have early gastric cancers not detectable (https://www.ncbi.nlm.nih.gov/books/NBK1139/) on endoscopy, and prophylactic total gastrectomy (PTG) is recommended, rather than endoscopic surveillance, in families with a history of the disease. However, PTG is controversial for families without gastric cancer because of its significant morbidity (https://jamanetwork.com/journals/jamaoncology/fullarticle/2737090), so they may be monitored with intensive endoscopic surveillance.
Prophylactic mastectomy is not recommended, but it may be a reasonable option for some women with an extensive family history of breast cancer, especially with diagnoses before age 45.
Increased screening: For at-risk individuals who are not ready for PTG, experts recommend the Cambridge protocol, a detailed 30-minute upper endoscopy every 6–12 months with multiple biopsies of random tissue and subtle lesions. Screening begins (https://www.ncbi.nlm.nih.gov/books/NBK1139/) 5–10 years prior to the youngest cancer diagnosis in the family. Ideally, it's performed by an endoscopist familiar with the Cambridge protocol in a center with experience caring for individuals with a CDH1 pathogenic variant.
Females should have annual breast magnetic resonance imaging (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) (MRI) starting at age 25–29. Bilateral breast MRI examination is also strongly recommended. At age 30 and beyond, begin alternating annual mammography and breast MRI every six months. A clinical breast exam (ideally by a breast surgeon) is recommended every 6–12 months starting at age 25. Begin educating patients on how to perform monthly breast self-examination at age 18, stressing the importance of prompt evaluation of any changes.
Obtain colonoscopy every three to five years, beginning at age 40 or 10 years prior to the youngest age of colon cancer diagnosis in families with histories of both HDGC and colon cancer.
Early identification of families with pathogenic CDH1 variants enables clinicians to offer them the best prevention and early detection strategies. Referral to support programs can help families with a pathogenic variant cope with extensive screening and risk-reducing surgeries: