Germline POT1 Variants in a Pan-Cancer Cohort

Germline likely pathogenic and pathogenic variants (LPV/PVs) in POT1 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 POT1 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 POT1 variants in a pan-cancer cohort and describe the associated phenotypes.

Germline exome data available for 19,315 patients with cancer from the Oncology Research Information Exchange Network (ORIEN) were assessed for POT1 LPV/PV. Data regarding cancer diagnoses were obtained for those with and without POT1 variants. Associations were assessed.

POT1 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 POT1-negative patients, those with POT1 LPV/PVs were 5.5-fold more likely to be diagnosed with PTC (95% CI, 1.9 to 15.1; P = .004) and 16.6-fold more likely to be diagnosed with CLL (95% CI, 6.4 to 41.9; P < .001). Patients with POT1 LPV/PVs had a younger median age of first cancer diagnosis compared with POT1-negative patients (P = .008).

To our knowledge, this study is the largest investigation of POT1 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.