Genomic Ascertainment of CHEK2-Related Cancer Predisposition

Area of Science:

• Genetics and Genomics
• Oncology
• Epidemiology

Background:

• Deleterious germline variants in CHEK2 are known to increase breast and prostate cancer risk.
• Evidence for CHEK2 variants' association with other cancers is limited or conflicting.

Purpose of the Study:

• To quantify the prevalence of CHEK2 germline pathogenic and likely pathogenic variants.
• To assess cancer risk and survival associated with these CHEK2 variants using genomic ascertainment.

Main Methods:

• A case-control study utilizing two large, exome-sequenced biobanks: UK Biobank (n=469,765) and Geisinger MyCode (n=167,050).
• Variants classified using American College of Medical Genetics and Genomics and Association for Molecular Pathology criteria.
• Association analysis performed with SAIGE-GENE+ adjusting for relatedness and using Bonferroni correction.

Main Results:

• Significant excess risk observed for all cancers, breast, prostate, kidney, bladder, and lymphoid leukemia in individuals with CHEK2 pathogenic variants.
• Time to cancer diagnosis was significantly shorter in cases compared to controls.
• Overall survival was decreased in UK Biobank cases, particularly after age 75; no significant survival difference was noted in MyCode.

Conclusions:

• Germline CHEK2 pathogenic variants are associated with an increased risk of multiple cancers, including breast, prostate, kidney, bladder, and lymphoid leukemia.
• The conferred excess mortality and cancer risk associated with these variants is relatively low (odds ratios <2).
• Findings have clinical implications for individuals identified with CHEK2 variants through genomic ascertainment, distinct from those with a family history of cancer.