Comprehensive genetic profiling reveals promising data on hereditary cancers

CHICAGO — Comprehensive genetic profiling identified germline inherited pathogenic variants in 3% to 7% of patients with hereditary cancers, according to study results presented at the ASCO Annual Meeting.

“We know that with next-generation sequence testing of wide panels of genes, there is a high likelihood of finding the right method to sort out not only the tumor-based genes and variants within those genes, but also germline mutations,” Michael J. Hall, MD, MS, director of gastrointestinal risk assessment at Fox Chase Cancer Center, told HemOnc Today. “We began to look at what potentially the prevalence or burden of germline pathogenic variants might be in people who get these tests.”

Next-generation sequencing-based comprehensive genetic profiling is an increasingly used tool for assessing patient eligibility for targeted therapies, according to study background. Although researchers previously studied the predictive accuracy of comprehensive genetic profiling in identifying germline or somatic status, the prevalence of germline variants in hereditary cancer genes and their potential clinical implications remained unreported.

Hall and colleagues evaluated data from 15,060 tumor samples. Researchers used criteria from the American College of Medical Genetics and focused on 20 penetrant hereditary cancer risk genes identified as high priority for disclosure upon discovery.

Researchers identified 521 unique variants and observed one or more germline variants in 30.8% (n = 4,633) of tumors tested. Researchers identified a likely pathogenic variant in 3.1% of tumors (n = 466). An additional 3.9% of tumors (n = 587) had suspicious variants confounded by conflicting data.

“Our estimates are very conservative, because we only included variants that we confirmed as variants through two databases,” Hall said. “There were many other variants that looked very suspicious but simply did not meet our criteria.”

Researchers observed a higher percentage of pathogenic variants compared with the general population in MUTYH (1.3% vs. 0.02%), RET (0.7% vs. 0.02%), BRCA1 (0.6% vs. 0.001%), BRCA2 (0.5% vs. 0.001%), MLH1 (0.02%), PMS2 (0.02% vs. 0.001%) and TP53 (0.02% vs. 0.0002%).

BRCA1 mutations exhibited the strongest association with early-onset cancer compared with the other pathogenic variants (P < .001).

Researchers observed the highest percentage of unexpected pathogenic variants in bladder cancer (4.1%), squamous cell lung cancer (4.4%) and kidney cancer (3.4%).

“There are probably 30 or 40 other genes we could still look at, which would then impact our prevalence rate,” Hall said. “I think, also, [comprehensive genetic profiling] will affect the way we impart information to cancer patients who are coming in to get these tumor profiles. We need to tell them that now that we are using these wide panels of genes, we are likely to find genes that will have implications not only related to their own health, but to the health of family members.” – by Cameron Kelsall

Reference:

Hall MJ, et al. Abstract 11084. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

For more information:

Michael J. Hall, MD, MS, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; e-mail: michael.hall@fccc.edu.

Disclosure: Foundation Medicine provided funding for this study. Hall reports research funding from Myriad Genetics, travel expenses from PAREXEL International and holding a patent to investigate hereditary colorectal cancer genes. Please see the abstract for a list of all other researchers’ relevant financial disclosures.