Gastric cancer risks due to CDH1 variant likely overestimated

By Marilynn Larkin

NEW YORK (Reuters Health) - 4/7/2019

The cumulative incidence of gastric cancer for individuals with a pathogenic CDH1 variant is lower than previously reported, according to a recent retrospective analysis.

"Our data suggests that individuals with pathogenic variants in CDH1 should think differently about risk when considering prophylactic gastrectomy," Dr. Brian Shirts of the University of Washington in Seattle told Reuters Health by email. "The immediate impact will be on patient counseling...Our results will allow for more personalized genetic counseling, which will lead to patients being able to make more informed decisions regarding their care."

"From personal communications," he said, "we know that many genetics professionals are skeptical about the accuracy of current risk estimates for patients who have been identified with CDH1 through screening and eager for more accurate population-based risk estimates."

Dr. Shirts and colleagues studied 238 individuals from 75 families with pathogenic variants in CDH1. Pedigrees from those families included cancer status for 1,679 relatives. Penetrance estimates were based on 41 families that had completed pedigrees available.

As reported online June 27 in JAMA Oncology, overall, participants' mean age was 49; 63% were women; ethnicity (reported for 89% of families) included 76% European and 6% each of Asian, African, Latino, and two or more ancestries.

Standardized incidence ratios for gastric and breast cancer were significantly elevated above Surveillance, Epidemiology, and End Results (SEER) incidence (i.e., incidence in the general population).

For those with pathogenic CDH1 variants, the extrapolated cumulative incidence of gastric cancer at age 80 was 42% for men and 33% for women; the cumulative incidence of female breast cancer was estimated at 55%.

International Gastric Cancer Linkage Consortium criteria were met in 25 of the 75 (33%) families; however, after dispensing with the requirement of confirmation of hereditary diffuse gastric cancer histologic subtype, 43 (57%) would meet the criteria.

Stratifying by the number of reported cases of gastric cancers per family, the estimated cumulative incidence was 27% for men and 24% for women reporting two or fewer gastric cancers; for those reporting three or more gastric cancers, the estimated cumulative incidence was 64% for men and 47% for women.

Further, colorectal cancer was estimated at 7% for men and 4% for women, which was not appreciably different from the 4.2% lifetime colorectal cancer risk in SEER.

The authors state, "Although the penetrance estimates in this study are not completely representative of unselected CDH1 pathogenic variant carriers, they are likely a better representation of the penetrance in families with less-severe cancer histories, allowing for more accurate risk assessment."

"Because prophylactic gastrectomy can have bearing upon both physical and psychological health, further discussion is warranted to assess whether this surgical recommendation is appropriate for all individuals with pathogenic variants in CDH1," they conclude.

Dr. Wei Zhang, Director, Cancer Genomics and Precision Oncology at Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem told Reuters Health, "This study illustrates the importance of combining germline pathogenic variant data obtained from DNA sequencing with family cancer history information to better inform patients and families of their relative risk to develop gastric cancer."

"The presence of CDH1 germline mutation alone, when the pathogenic capacity ranking is not currently in place, is not sufficient and may lead to overestimation of the risk," he said by email. "This study reflects a need for genetic counseling to become more precise because the prophylactic intervention can be very dramatic and have serious life quality consequences."


JAMA Oncol 2019.

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