Prevalence of incidental germline variants detected via tumor-only mesothelioma genomic profiling
Authors: Mitchell Owen D. , Gilliam Katie , Gaudio Daniela del , McNeely Kelsey E. , Smith Shaili , Acevedo Maria , Gaduraju Meghana , Hodge Rachel , Ramsland Aubrianna S.S. , Segal Jeremy , Das Soma , Bryan Darren S. , Tawde Sanjukta , Galasinski Shelly , Wang Peng , Tjota Melissa Y. , Husain Aliya N. , Armato Samuel , Donington Jessica , Ferguson Mark K. , Turaga Kiran , Churpek Jane E. , Kindler Hedy L. , Drazer Michael W. 
Published: December 2022

Structured AbstractImportancePatients 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.ObjectiveTo determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.DesignA 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.SettingThis was an observational study from a high-volume mesothelioma program. All patients enrolled on Institutional Review Board-approved protocols.Participants161 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 Outcome(s) and Measure(s)The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.ResultsMost (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 inATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, andTMEM127.Conclusions and RelevanceMost (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.Key PointsQuestionWhat proportion of patients with mesothelioma have pathogenic or likely pathogenic germline variants incidentally identified by tumor-only genomic profiling?FindingsIn this cohort study of 161 patients with mesothelioma, 78% of patients had potential germline variants that warranted further evaluation. Overall, 16% of patients had pathogenic or likely pathogenic germline variants initially identified via tumor-only genomic profiling.MeaningTumor genomic profiling of mesothelioma frequently (78% of patients) identifies potential germline pathogenic/likely pathogenic variants that warrant dedicated germline evaluation. The high prevalence of germline variants (16%) in our series suggests universal genetic testing may be warranted for patients with mesothelioma.