Prevalence of incidental 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 Outcome(s) and Measure(s) 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. Question What proportion of patients with mesothelioma have pathogenic or likely pathogenic germline variants incidentally identified by tumor-only genomic profiling? Findings In 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. Meaning Tumor 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. ### Competing Interest Statement D.G and S.D operate a clinical genetics laboratory that offers a hereditary mesothelioma diagnostic assay. H.L.K reports consulting/advisory roles with AstraZeneca, Tempus, Bluestar Genomics, Sanofi, Novocure and Deciphera. M.W.D reports consulting roles with Cardinal Health and Argenx. All other authors have no relevant conflicts of interest to declare. ### Funding Statement This work was supported by three grants awarded to M.W.D: The Cancer Research Foundation Young Investigator Award, a NIH K12 Paul Calabresi Award and The University of Chicago Comprehensive Cancer Center Cooney Mesothelioma Research Award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of The University of Chicago Biological Sciences Division/University of Chicago Medical Center (FW00005565) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript