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Abstracts highlight importance of identifying, managing germline mutations in patients with somatic genomic testing of cancer
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A series of at least five unrelated abstracts presented at this year’s ASCO Annual Meeting — including the one by Hall and colleagues — underscores the importance of identifying, and appropriately managing, germline mutations conferring risk for heritable cancer that are incidentally found in somatic genomic testing of cancer tissues.
Apart from the Hall and colleagues abstract, there are at least three others presented by Meric-Berstam and colleagues, Schrader and colleagues, and Barton and colleagues, that analyzed the frequency of germline mutations in American College of Medical Genetics-designated actionable heritable cancer genes found incidentally on somatic testing of 2,681 tumors not included in the Hall series. Of these 2,681 tumors, 188 (7%) were believed to carry a germline “likely” pathogenic variant/mutation. Typically, a small subset of these patients had already been referred to cancer genetics consultation. It is unclear — except for the abstracts by Barton and colleagues and Funchain and colleagues — whether the incidental identification of germline mutations led to systematic referral to cancer genetics evaluation. Without the advantage of separate germline testing, at least two of these studies looked for clues that could help predict prior probability of finding a germline mutation. Hall and colleagues identified young age of onset, particularly with incidental BRCA1 mutations, whereas Funchain and colleagues identified a mutant allelic fraction greater than 35%.
It is well known for longer than 3 decades that a mean of 5% of all patients with cancer will have a germline mutation associated with heritable cancer. Indeed, these five studies suggest that a mean of 7% (range 3.1-16) likely carried germline mutations in cancer risk genes. Finding germline mutations for hereditary cancers have clinically actionable implications for both patient and family. Relying on ad hoc referral to cancer genetics services has been haphazard with less than perfect ascertainment. Could these studies suggest that glimmer of hope whereby the germline fallout of somatic testing could serve as a systematic screen for referral to cancer genetics evaluation and management?
If this is to become a viable and reliable mechanism, then several things need to occur. First, the germline and somatic tissue should be analyzed. Second, experts who can interpret germline variation need to interpret the germline genomic testing. Germline and somatic variant interpretation are vastly different. Third, genomic tumor boards must include cancer genetic professionals, whether formally trained MD clinical cancer geneticists or cancer genetic counselors. Fourth, interdisciplinary consensus criteria — which comprise demographic, clinicopathologic and/or genomic factors — for referral to cancer genetics evaluation should be standardized. Finally, cancer genetics clinical services must be able to rapidly see such referrals, perhaps within 1 to 3 days.
References:
Barton LV, et al. Abstract e12552.
Funchain P, et al. Abstract 1523.
Hall MJ, et al. Abstract 11084.
Meric-Berstam F, et al. Abstract 1510.
Schrader KA, et al. Abstract 1509.
For more information:
Charis Eng, MD, PhD, is professor and chair of the Cleveland Clinic Genomic Medicine Institute and the HemOnc Today’s molecular oncology section editor. She can be reached at engc@ccf.org.
Disclosure: Eng reports no relevant financial disclosures.