Biological Sciences Division
Published August 9, 2023 | Version v1
Journal article Open

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

Creators

  • 1. University of Chicago
  • 2. University of Wisconsin, Madison

Description

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.

Data availability

See Supplement 2.

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Additional details

Identifiers

DOI
10.1001/jamanetworkopen.2023.27351
Other
oai:uchicago.tind.io:11232

Funding

Cancer Research Foundation
Young Investigator Award
National Institutes of Health
K12 Paul Calabresi Award
University of Chicago
Comprehensive Cancer Center Cooney Mesothelioma Research Award

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Human Genetics, Medicine, Pathology, Radiology, Surgery