Abstract
AbstractPurposeThere is clear evidence that deleterious germline variants inCHEK2increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk inCHEK2germline pathogenic variant heterozygotes.Patients and MethodsGermlineCHEK2variants 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 aCHEK2pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benignCHEK2variation or wildtypeCHEK2. Tumor phenotype and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction.ResultsInCHEK2heterozygotes 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 inCHEK2heterozygotes 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 inCHEK2heterozygotes in UK Biobank but there was no statistical difference in MyCode.ConclusionUsing genomic ascertainment in two population-scale cohorts, this investigation quantified the prevalence, penetrance, cancer phenotype and survival inCHEK2heterozygotes. Tailored treatment options and surveillance strategies to manage those risks are warranted.
Publisher
Cold Spring Harbor Laboratory