E-cadherin mutations linked to increased gastric, breast cancer risk

Last Updated: 2015-02-17

By Will Boggs MD

NEW YORK (Reuters Health) - Mutations in the E-cadherin gene (CDH1) in families with hereditary diffuse gastric cancer (HDGC) are associated with significant increases in the lifelong risk of gastric and breast cancer, researchers report.

"Families with a strong history should be referred for testing," Dr. David G. Huntsman, from British Columbia Cancer Agency and University of British Columbia, Vancouver, told Reuters Health by email. "Follow-up of unaffected mutation-positive individuals should be led by a multidisciplinary team including a geneticist, gastroenterologist, dietician, genetic counselor, and surgeon."

HDGC is characterized by early-onset, multigenerational diffuse gastric cancer and lobular breast cancer, and about 40% of families carry germline mutations in CDH1. The extent to which carriage of CDH1 mutations affects future cancer risk remains uncertain.

Dr. Huntsman's team tested 183 index cases with HDGC for CDH1 germline mutations in an effort to derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and to determine if germline mutations in other genes are associated with HDGC.

Thirty-four of these cases (19%) had 31 germline pathogenic CDH1 mutations, including 17 previously reported and 14 novel mutations, all of them heterozygous.

The cumulative incidence of gastric cancer by age 80 years was 70% for men and 56% for women with CDH1 mutations, and the risk of breast cancer by age 80 years was 42% for women, according to the February 12 JAMA Oncology online report.

Sixteen other HDGC cases (11.1%) had non-CDH1 mutations, including novel truncating mutations in CTNNA1, a novel BRCA2 truncating variant, a truncating mutation in PRSS1, heterozygous protein-truncating variants in ATM and PALB2, and missense variants in SDHB, STK11, and MSR1.

"Compared with several previously published reports, our results reveal less than half the expected numbers of HDGC families investigated have a germline CDH1 mutation," the researchers note. "This number could be a reflection of the varied ethnicities within our consecutive series; it is well known that the frequency is highly variable between countries with different incidences of gastric cancer, and prior ascertainment of kindred with the strongest family histories may have skewed past reports."

How should we manage these individuals with CDH1 mutations? "Since screening has not proven to be sensitive enough and the cancers are lethal if high stage, then prophylactic gastrectomy should be considered," Dr. Huntsman said.

The best approach for those without CDH1 mutations remains uncertain. "Without mutations there is no way of segregating risk in the families or determining whether the clustering of cancers that led to testing was a chance occurrence or indicative of high but undefined risk," Dr. Huntsman said. "Advice would be influenced by the strength of the family history. Usually endoscopic screening and random biopsies every couple of years is recommended if the family history is very strong."

"More genetic research is needed to identify the susceptibility genes that likely cause the gastric cancer clustering in CDH1-negative families," Dr. Huntsman said.

"Also of importance, no evidence was found for risk of other cancer types in individuals with a CDH1 mutation," writes Dr. James M. Ford from Stanford University School of Medicine, Stanford, California, in a related commentary.

"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," Dr. Ford said. "Current guidelines suggest breast cancer screening using annual magnetic resonance imaging starting at age 30 years and consideration of prophylactic total gastrectomy 5 years younger than the youngest case in the family, with endoscopic screening recommendations remaining poorly defined."

Dr. Fatima Carneiro, from University of Porto, Porto, Portugal, recently reviewed the genetic susceptibility and pathology of familial gastric cancer. She told Reuters Health by email, "Individuals who tested positive for a germline CDH1 pathogenic mutation should be advised to consider prophylactic gastrectomy, regardless of any endoscopic findings (due to the lack of effective endoscopic surveillance). The timing of surgery may vary according to the individual's preference and age, as well as to his/her physical and psychological fitness."

"Families meeting phenotypic criteria for HDGC with mutations in genes other than CDH1 and CDH1-like genes, will most likely benefit from carrier risk-reduction strategies based on the mutated gene (i.e., BRCA2)," Dr. Carneiro said.

Dr. Carneiro added, " more precise estimates of age-associated risks of gastric and breast cancer will improve counseling of unaffected carriers. It is also very relevant to finding of genes, other than CDH1, in families fulfilling the clinical criteria of HDGC."

This research was supported by a number of Canadian organizations. Three authors report receiving support from the Canadian Institutes of Health and Portuguese Foundation for Science and Technology.

SOURCE: http://bit.ly/1uJRDeo and http://bit.ly/1FDMKor

JAMA Oncol 2015.