Abstract
PURPOSE: There is clear evidence that deleterious germline variants in CHEK2 increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in CHEK2 germline pathogenic variant heterozygotes. PATIENTS AND METHODS: Germline CHEK2 variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503). Variants were classified as per American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria. Heterozygotes harbored a CHEK2 pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benign CHEK2 variation or wildtype CHEK2. Tumor phenotype and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction. RESULTS: In CHEK2 heterozygotes in both MyCode and UK Biobank, there was a significant excess risk of all cancers tested, including breast cancer (C50; OR=1.54 and 1.84, respectively), male genital organ cancer (C60-C63; OR=1.61 and 1.77 respectively), urinary tract cancer (C64-C68; OR=1.56 and 1.75, respectively) and lymphoid, hematopoietic, and related tissue cancer (C81-C96; OR=1.42 and 2.11, respectively). Compared to controls, age-dependent cancer penetrance in CHEK2 heterozygotes was significantly younger in both cohorts; no significant difference was observed between the penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased in CHEK2 heterozygotes in UK Biobank but there was no statistical difference in MyCode. CONCLUSION: Using genomic ascertainment in two population-scale cohorts, this investigation quantified the prevalence, penetrance, cancer phenotype and survival in CHEK2 heterozygotes. Tailored treatment options and surveillance strategies to manage those risks are warranted.