Exome Sequencing Highlights Hidden Breast-, Ovarian-Cancer Risks

By David Douglas

NEW YORK (Reuters Health) - Exome sequencing in more than 50,000 people shows that hereditary variants in the BRCA1/2 genes associated with breast and ovarian cancer may be more common than thought.

In a paper online September 21 in JAMA Network Open, Dr. Michael F. Murray of Yale School of Medicine, in New Haven, Connecticut, and colleagues note that risk-assessment strategies, based on personal and family-history cancer thresholds, are routinely used to identify people with increased pretest probability of pathogenic BRCA1/2 variants.

However, failure to apply these guidelines and other factors may reduce the identification of true positives even in women with existing cancer diagnoses.

To obtain further information on the true distribution of pathogenic and likely pathogenic variants, the team conducted whole-exome sequencing in 50,726 predominantly white members of a single healthcare system.

In 99.5% no expected pathogenic BRCA1/2 variants were seen, while the remaining 0.5% were BRCA1/2 carriers; 95 had BRCA1 variants and 172 patients had BRCA2 variants.

Of these cases, 148 were women and 119 were men. Their mean age was 58.9 years. Overall, 82.0% of the variant carriers had had no prior clinical testing.

A number of participants died before results were available, but 11 (47.8%) of the 23 deceased BRCA1/2 carriers and 56 (20.9%) of all carriers had had diagnoses of syndromic cancer.

In women, 20.9% of the variant carriers had a personal history of breast cancer, compared to 5.2% of noncarriers (odds ratio, 5.95). Corresponding values for ovarian cancer were 10.1% and 0.6% (OR, 18.30).

In addition, of the 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family-history data, almost half did not meet published guidelines for clinical testing.

"The prevalence of BRC1/2 variants in the general population may be substantially higher than was previously estimated, and reliance on personal and family history may be an inadequate measure to ascertain risk," the researchers conclude.

Dr. Timothy R. Rebbeck of the Dana Farber Cancer Institute, in Boston, who was not involved in the research, told Reuters Health by email, "This is one of the first major studies to comprehensively evaluate mutations in BRCA1 and BRCA2 in a large sample of adults unselected for cancer risk. As such it is an important reference guide to the prevalence of mutations in the U.S. population. The 0.5% prevalence is higher than has been reported in most other populations to date."

"This study also confirms the observation that a large proportion of individuals who test positive for these mutations do not meet testing criteria - they would probably not have been tested under usual protocols," added Dr. Rebbeck, who is also professor of cancer prevention at Harvard T.H. Chan School of Public Health.

He said the findings may be an argument for wider, perhaps population-based testing. "However, the mutations are still very rare, so true population-based testing may still not be cost-effective. More research needs to be done."

Also, he noted, "it may be worthwhile to test using broader panels rather than just test for one or a few genes, since we tend to find a lot of clinically important mutations in genes in which we did not expect to find a mutation."

Dr. Deanna J. Attai, assistant clinical professor of surgery at the David Geffen School of Medicine at the University of California, Los Angeles, said current guidelines and testing practices may "result in patients who will not be identified for potentially life-saving intensive screening and/or prophylactic surgeries."

"Despite some of the described study limitations, (the new) research adds to those voices who are calling for broadening of existing genetic testing criteria or for universal testing," Dr. Attai, who also was not involved in the study, told Reuters Health by email.

Dr. Murray did not respond to requests for comments.

SOURCE: https://bit.ly/2xuzhDf

JAMA Netw Open 2018.

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