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Study of Mutations in CDH1, Other Genes Provides Better Estimate of Inherited Gastric Cancer Risk

NEW YORK (GenomeWeb) – New research has yielded a much more precise estimate of the lifetime risk of gastric and breast cancers in people who have hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome, and who carry a mutation in the gene CDH1.

The study, led by researchers from the Universityof British Columbia and published today in the newly-launched journal JAMA Oncology, determined that the cumulative risk of gastric cancer for men with these mutations is 70 percent by age 80, while for women it is 56 percent.

It also identified a set of new alterations associated with HDGC-associated cancers in those who are CDH1 mutation-negative, information that could be used to help counsel patients who meet clinical criteria for HDGC but lack a CDH1 mutation.

Prior to the UBC team's study, estimates of the cumulative lifetime cancer risk in CDH1 mutation carriers were derived from only a small number of families, the authors wrote, with predicted risks ranging widely — from 40 percent to 67 percent in men, and from 63 percent to 83 percent in women.

In their expanded study, the researchers were able to provide what they believe is now the most accurate estimate of the risk of gastric and breast cancers for people with these mutations to date.

To make these calculations, the group recruited 183 new index cases between 2006 and 2013 to undergo CDH1 testing. Overall, 34, or about 19 percent of the 183 index cases were found to have germline pathogenic CDH1 mutations, while four were determined to have CDH1 variants of unknown significance. Ten of the 34 mutation-positive cases had mutations that had been previously reported in other patients.

According to the authors, this rate of CDH1 mutations is less than half that seen in previous studies, which have implied that CDH1 mutations occur in closer to 40 percent of HDGC families.

In order to estimate the penetrance of CDH1 mutations, the group looked at 75 newly identified mutation-positive families combined with data from other study groups comprising 3,858 individuals in total.

Based on the results, the team determined that by 80 years of age, the cumulative incidence of gastric cancer for male carriers of CDH1 mutations is 70 percent. For female carriers, gastric cancer risk is 56 percent and breast cancer risk is 42 percent.

The researchers then tested a group of 144 CDH1 mutation-negative HDGC subjects using a targeted sequencing panel covering 55 genes. Sixteen of the 144 patients were found to harbor candidate mutations in one of these genes, including mutations in several genes of high and moderate penetrance.

The authors wrote that among these, CTNNA1 mutations, found in two unrelated families from the cohort, are the most likely to mirror the genetic and functional significance of CDH1 mutations in HDGC.

Like CDH1, CTNNA1 is involved in intercellular adhesion, and is a suspected tumor suppressor, the authors wrote.

The analysis also identified a potentially pathogenic germline mutation in BRCA2, and mutations in other genes associated with other hereditary cancer predisposition syndromes, including STK11, PALB2, and ATM.

Based on the results, the researchers proposed that genetics — for example the presence of CDH1 mutations or alterations of closely related genes like CTNNA1 — rather than clinical factors, may be a more useful way to define HDGC and guide risk reduction strategies for families.

In other words, clinically or phenotypically defined HDGC may actually comprise several subsets of genetically defined cancer susceptibility syndromes.

"Despite meeting phenotypic criteria for HDGC… families with mutations in other genes would most likely benefit from carrier risk reduction strategies bases on the mutated gene rather than the cancer types that lead to the referral," they wrote.

Additional research will be necessary to determine the risk conferred by mutations in genes other than CDH1 in order for them to be clinically useful, the researchers noted.