Precise risk assessment for gastric and breast cancers among CDH1 gene mutation carriers may improve genetic counseling

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More precise estimates of age-associated risks of gastric and breast cancer were derived for carriers of the CDH1 gene mutation, a cancer-predisposing gene that is abnormal in families meeting criteria for clinically defined hereditary diffuse gastric cancer (HDGC), according to a study published online by JAMA Oncology (2015; doi:10.1001/jamaoncol.2014.168).

Gastric cancer (GC) is the third most common cause of cancer-related death in the world. HDGC is characterized by its early onset and multigenerational nature, as well as lobular breast cancer.

Current cumulative lifetime GC risk in CDH1 mutation carriers is derived from a small number of families with predicted risks of 40% to 67% in men and 63% to 83% in women. Female carriers also have 39% to 52% risk of breast cancer risk.

The only recommended ways to reduce the risk of GC is screening gastroscopy with multiple random biopsies or surgical removal of the entire stomach to prevent cancer, according to the study background.

David G. Huntsman, MD, of the British Columbia Cancer Agency, Canada, and coauthors tested for CDH1 germline mutations in 183 new families with HDGC. Penetrance—the proportion of people with a gene mutation who will show clinical disease—was derived from 75 mutation-positive families from this and other study groups comprising 3,858 persons. Germline DNA from 144 HDGC families without the CDH1 mutations also were screened for 55 cancer-associated genes to determine if other genes are associated with HDGC.

The authors identified 31 distinct CDH1 mutations (14 of them novel) in 34 of 183 families (19%). They estimate that by the age 80 years, the cumulative incidence of gastric cancer is 70% for men and 56% for women, with a 42% risk of breast cancer for women. Researchers also identified candidate mutations in 16 of 144 probands (the person who is the starting point in a family being studied), including mutations within genes of high and moderate penetrance.

“These data should assist in the genetic counseling and management of at-risk individuals from CDH1-positive HDGC families,” the study concluded.

An accompanying editorial (doi:10.1001/jamaoncol.2014.187) by James M. Ford, MD, of the Stanford University School of Medicine, California, stated, “The article by Hansford [and colleagues] assembles the largest group of genetically defined HDGC families to date (75 families, comprising 3,858 individuals) to determine age-specific penetrance of gastric and breast cancers. … These updated risk assessments should be considered the new standard for genetic counseling and will be included in the next International Gastric Cancer Linkage Consortium guidelines.”

“The current article by Hansford [and colleagues] provides a major advance. Further clinical and genetic research is necessary to identify biomarkers and better methods of screening individuals at high risk,” Ford concluded.

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