Frequency of incidental pathogenic and likely pathogenic germline variants detected via tumor-only mesothelioma genomic profiling

Importance: Patients with mesothelioma often have next generation sequencing (NGS) of their tumor. Tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS. Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma. Design: A series of 161 unrelated patients with mesothelioma had tumor-only NGS and germline NGS. These assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Setting: This was an observational study from a high-volume mesothelioma program. All patients enrolled on Institutional Review Board-approved protocols. Participants: 161 unrelated patients with pleural, peritoneal, or bicavitary mesothelioma. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): No therapeutic interventions were used. Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS. Results: Most (78%) patients had potentially incidental P/LP germline variants. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 16% of patients carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127. Conclusions and Relevance: Most (78%) patients with mesothelioma had potentially incidental germline P/LP variants on tumor NGS, but the positive predictive value of these was modest (20%). Of all patients, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.