Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol

Abstract

Background: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs).Patients and methods: Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.Results: Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing. Conclusions:In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancerrelated genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.

Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

“…Potentially unsuspected pathogenic variants have now been reported in a small, but not insignificant, proportion of cancer patients undergoing therapeutically indicated tumor-germline testing(10,11), and our data provide further support to this scenario. Disclosing the identification of a hereditary cancer predisposition would be highly relevant to the clinical care of these cancer patients and have important implications for their relatives’ medical guidance.…”

“…In the course of tumor/germline sequencing, the incidental detection of germline mutations of potentially diagnostic clinical significance can and does occur as previously described by other groups (10,11). As these concomitant and potentially unexpected findings could have significant implications for the patient and their family members, we conducted an exploratory study within patients undergoing tumor-germline sequencing to explore the frequency of “opportunistically identified” pathogenic germline variants within cancer predisposing genes.…”

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

“…11,12 However, we observed potentially deleterious somatic alterations in DNA damage repair genes, BRCA1/2 , PALB2 , ATM and RAD51 . Further, we observed alterations in several genes associated with the SWI/SNF complex or other epigenetic processes including BAP1 , ARID1A , DNMT3A and EP300 .…”

Discrimination of Germline EGFR T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients

“…Reporting clinically significant germline findings incidental to somatic genomic testing in cfDNA may provide clinical benefits to advanced cancer patients. In a large tissue-based pan-cancer NGS study, 2.3% of patients were found to have previously unrecognized pathogenic germline variants (21). Additionally, numerous reports in non-lung cancers have found significant rates of potentially targetable germline alterations in patients who would not be screened on the basis of family history, particularly in DNA repair genes (22–25).…”