Yale researchers have shown that individuals who carry a mutation in the CDH1 gene have a 30% to 40% risk of developing stomach cancer during their lifetime. Yet many people with the rare mutation remain unaware that they have it. Stomach cancer, also known as gastric cancer, is the fifth most common type of cancer in the world. While common in South America and East Asia, the cancer is relatively rare in the U.S. Diffuse gastric cancer, the type of stomach cancer associated with mutations in the CDH1 gene, tends to grow and spread within the lining of the stomach, said Benjamin Lerner, MD, MHS, assistant professor of medicine (digestive diseases). This cancer often presents with vague symptoms and doesn’t always form a bulky tumor, he added, and as a result, tends to be diagnosed late, resulting in a poor prognosis. “Approximately 10% of gastric cancers cluster in families, and in 1% to 3% of gastric cancers, we can identify a gene mutation and classify it into a genetic cancer syndrome,” Lerner explained. “Hereditary diffuse gastric cancer (HDGC), an inherited condition associated with early onset diffuse gastric cancer and lobular breast cancer, is most often caused by mutations in the CDH1 gene.” Currently, the accepted guidelines for CDH1 testing involve nine criteria. Working alongside his mentor Xavier Llor, MD, PhD, professor of medicine (digestive diseases) and director of the Gastrointestinal Cancer Prevention Program, and colleague Rosa Munoz Xicola, PhD, assistant professor of medicine (digestive diseases), Lerner set out to evaluate whether these criteria were adequately identifying those at risk for HDGC. We had the sense that the current criteria are overly restrictive and probably not capturing many of the individuals who have the mutation that causes HDGC.Benjamin Lerner, MD, MHS “We had the sense that the current criteria are overly restrictive and probably not capturing many of the individuals who have the mutation that causes HDGC,” Lerner said. “In addition, the current guidelines call for health information about family members, which can be difficult for patients or health care providers to obtain.” In their study, the Yale team found that among 112 patients with CDH1 mutations, only about 20% would have been identified using the current testing criteria. The findings led the team to develop simpler criteria to reach a larger percentage of CDH1 mutation carriers. The new Yale criteria has two components, according to Lerner. “First, since diffuse gastric cancer is a small slice of total gastric cancer cases, we recommend genetic testing for anyone who is diagnosed with diffuse gastric cancer,” he said. “Second, we recommend testing for anyone who has at least two cases of gastric cancer in first- or second-degree relatives, as long as one of those relatives was diagnosed by age 50.” The Yale researchers also recommend that health care providers pay attention to other genetic testing guidelines. “It’s important to look at HDGC within the broader context of cancer genetics,” Lerner said. “The National Comprehensive Cancer Network, for instance, recommends testing for mutations in CDH1, among other genes, in cases of suspected hereditary breast cancer.” The team hopes their new criteria will be adopted widely to further understanding of this rare genetic condition. “We still have a lot of questions about how best to manage individuals with HDGC,” Lerner said. “The new criteria will not only work to prevent cancer in more people but also allow us to explore a variety of approaches that will impact how we treat patients in the future.” Since forming one of the nation’s first sections of hepatology more than 75 years ago and then gastroenterology nearly 70 years ago, Yale School of Medicine’s Section of Digestive Diseases has had an enduring impact on research and clinical care in gastrointestinal and liver disorders. To learn more about their work, visit Digestive Diseases.