Cancer risk and survival outcomes in germline POT1 variant carriers

Background: The prevalence of germline POT1 variants, spectrum of associated tumors, cancer risk and survival outcomes are incompletely described, and clinical management guidelines vary. We evaluated POT1 variant carriers in three biobanks and a clinical cohort to address these limitations. Methods: Prevalence, cancer spectrum and risk associated with germline POT1 pathogenic/likely pathogenic and additional functionally assessed variants were evaluated in Penn Medicine Biobank (PMBB; n=51,172), Geisinger MyCode (MyCode; n=220,582), UK Biobank (UKBB; n=469,558) and a Penn Medicine clinical cohort. Results: Estimated POT1 variant prevalence ranged from 1:1,279 to 1:2,902. Compared to non-carriers, cancer diagnoses were more frequent among POT1 variant carriers in PMBB (OR 3.41, 95%CI 1.81-6.43, p=1.88x10-4), MyCode (OR 2.23, 95%CI 1.31-3.79, p=0.003), and UKBB (OR 1.40, 95%CI 1.07-1.84, p=0.015). Cancer incidence increased beginning in the mid-30s, without evidence of increased mortality. Along with previously described cancer types, lung cancer was associated with POT1 variant carriers in two biobank cohorts. Conclusion: POT1 is a cancer susceptibility gene associated with a moderate (1.5-3.5-fold) increased cancer risk. Variants are relatively frequent and predispose to a broad tumor spectrum and increased incidence starting in the mid-30s, without increasing mortality. These findings expand understanding of POT1-associated disease and provide data to inform clinical management.