Germline Variants in a Pan-Cancer Cohort.

[PURPOSE] Germline likely pathogenic and pathogenic variants (LPV/PVs) in have been associated with an increased risk of various cancers including angiosarcoma, melanoma, glioma, thyroid cancer, and chronic lymphocytic leukemia (CLL). However, to date, most of the published data regarding PVs involve cohorts of patients selected for specific cancer types, or stem from commercial laboratory cohorts from patients selected for germline clinical testing, which may cause ascertainment biases. The objective was to identify germline variants in a pan-cancer cohort and describe the associated phenotypes.

[METHODS] Germline exome data available for 19,315 patients with cancer from the Oncology Research Information Exchange Network (ORIEN) were assessed for LPV/PV. Data regarding cancer diagnoses were obtained for those with and without variants. Associations were assessed.

[RESULTS] LPV/PVs were identified in 23 patients. The cancer types seen in more than one patient include CLL (n = 7), papillary thyroid cancer (PTC, n = 5), colorectal cancer (n = 3), lung cancer (n = 3), glioblastoma (n = 2), and neuroendocrine tumors (n = 2). Compared with -negative patients, those with LPV/PVs were 5.5-fold more likely to be diagnosed with PTC (95% CI, 1.9 to 15.1; = .004) and 16.6-fold more likely to be diagnosed with CLL (95% CI, 6.4 to 41.9; < .001). Patients with LPV/PVs had a younger median age of first cancer diagnosis compared with -negative patients ( = .008).

[CONCLUSION] To our knowledge, this study is the largest investigation of germline variants in a pan-cancer cohort. We identify and confirm specific associations with CLL and PTC in this cohort. Differences in results between analysis of largely unselected cohorts compared with clinical testing cohorts highlight the need to study gene-cancer associations in more unselected populations.