Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma

JAMA Network Open 2023 August 1 [Link]

Owen D Mitchell, Katie Gilliam, Daniela Del Gaudio, Kelsey E McNeely, Shaili Smith, Maria Acevedo, Meghana Gaduraju, Rachel Hodge, Aubrianna S S Ramsland, Jeremy Segal, Soma Das, Feighanne Hathaway, Darren S Bryan, Sanjukta Tawde, Shelly Galasinski, Peng Wang, Melissa Y Tjota, Aliya N Husain, Samuel G Armato 3rd, Jessica Donington, Mark K Ferguson, Kiran Turaga, Jane E Churpek, Hedy L Kindler, Michael W Drazer


Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; 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, setting, and participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.

Main outcomes and measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.

Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) 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: In this case series of 161 patients with mesothelioma, 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.