Characterization of findings on prostate cancer tumor sequencing that should prompt consideration for germline testing.

Abstract

5022 Background: Tumor sequencing is increasingly used for therapeutic selection in men with advanced prostate cancer (PC). If tumor-only sequencing is performed without matched germline, identified mutations could be of somatic or germline origin. Germline mutations could confer additional risk for other cancers to the patient and at-risk family members. The objective of this study is to determine the overall and gene-specific probability of pathogenic/likely pathogenic germline mutations based on tumor-only sequencing. Methods: We investigated mutations found in a cohort of men with PC who underwent targeted next generation sequencing of PC tumor and matched peripheral blood using the MSK-IMPACT assay between 01/2015 and 01/2020. A germline probability for each gene was determined by dividing the number of germline mutations by the total number of somatic and germline mutations. Cancer susceptibility genes commonly sequenced on tumor-based tests for PC were assessed, including ATM, BRCA1/ 2, BRIP1, CHEK2, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2 (henceforth referred to as PC genes). Results: A total of 1883 men with PC were included, with median age of diagnosis of 62.0 ± 8.8 years. 84% had high risk PC, 52% had metastasis, 38% had family history of PC. A total of 364 (19%) men had at least one mutation (either somatic or germline) in PC genes. Overall, 189 (10%) men had at least one germline mutation that would not have been reported as germline without matched normal. The average germline probability of PC genes was 40% (range: 0% in MLH1 to 83% in CHEK2). The number of total mutations, germline mutations, and germline probability of genes found in > 0.5% of the study cohort are summarized in Table. All these genes are moderate/high penetrance autosomal dominant genes with established guidelines for cascade testing, enhanced cancer screening, or potential risk-reducing surgery. Conclusions: In this study, an average of 40% of mutations found in cancer susceptibility genes on PC tumor sequencing were germline mutations. Men undergoing tumor-only sequencing should be counseled on the possibility of uncovering a germline mutation. In addition to BRCA1/ 2, mutations in certain genes, such as CHEK2 and PALB2, have a high probability of being germline and should prompt referral for genetic counseling and germline testing.[Table: see text]