JAMA Netw Open. 2025 Dec 1;8(12):e2549730. doi: 10.1001/jamanetworkopen.2025.49730.
ABSTRACT
IMPORTANCE: There is clear evidence that deleterious germline variants in CHEK2 increase risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers.
OBJECTIVE: To quantify the prevalence of as well as cancer risk and survival associated with CHEK2 germline pathogenic and likely pathogenic variants using genomic ascertainment.
DESIGN, SETTING, AND PARTICIPANTS: This case-control study used 2 electronic health record-linked and exome-sequenced biobanks: UK Biobank (n = 469 765) and Geisinger MyCode (adults only; n = 167 050). Variants were classified according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Cases were defined as individuals with heterozygous CHEK2, harboring pathogenic or likely pathogenic variants; controls as individuals with a benign or likely benign CHEK2 variation or wildtype CHEK2. Cancer registry (MyCode since approximately 1943; UK Biobank since approximately 1970) and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction.
MAIN OUTCOMES AND MEASURES: Prevalence of as well as cancer risk and survival in adults with CHEK2 germline variants.
RESULTS: Of 469 765 individuals in the UK Biobank, there were 3232 case participants (mean [SD] age, 70.8 [8.0] years; 3139 [97.1%] White; 1744 [54.0%] women); of 167 050 individuals with MyCode, there were 3153 case participants (mean [SD] age, 60.5 [17.8] years; 3123 [98.8%] White; 1935 [61.5%] women). In case participants in both MyCode and UKBB, there was a significant excess risk of all cancers (odds ratio [OR], 1.33 [95% CI, 1.18-1.49]; OR, 1.41 [95% CI, 1.26-1.59], respectively), breast (OR, 1.54 [95% CI, 1.18-2.00]; OR, 1.84 [95% CI, 1.49-2.27], respectively), prostate (OR, 1.62 [95% CI, 1.27-2.07]; OR, 1.78 [95% CI, 1.48-2.16], respectively), kidney (OR, 1.58 [95% CI, 1.03-2.41]; OR, 1.84 [95% CI, 1.22-2.77], respectively), and bladder (OR, 1.50 [95% CI, 1.01-2.23]; OR, 1.64 [95% CI, 1.17-2.31], respectively) cancers as well as lymphoid leukemia (OR, 2.08 [95% CI, 1.17-3.69]; OR, 2.21 [95% CI, 1.19-4.08], respectively). Compared with control participants, time to cancer in case participants was significantly shorter in both cohorts; no significant difference was observed between the age-dependent penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased in case participants in UK Biobank; however, the primary consequence was seen after 75 years. There was no statistical difference in survival in MyCode. There were no differences in survival between case participants with cancer and control participants with cancer.
CONCLUSIONS AND RELEVANCE: In this case-control study of genomic ascertainment of individuals with heterozygous CHEK2 pathogenic or likely pathogenic variants in 2 population-scale cohorts, there was a significant excess risk of breast, prostate, kidney, bladder, and lymphoid leukemia cancer. The conferred excess mortality and cancer risk was low (ORs <2). This has clinical implications for individuals ascertained this way (vs with a family history of cancer).
PMID:41396600 | DOI:10.1001/jamanetworkopen.2025.49730
