Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.
Karlsson Q., Brook MN., Dadaev T., Wakerell S., Saunders EJ., Muir K., Neal DE., Giles GG., MacInnis RJ., Thibodeau SN., McDonnell SK., Cannon-Albright L., Teixeira MR., Paulo P., Cardoso M., Huff C., Li D., Yao Y., Scheet P., Permuth JB., Stanford JL., Dai JY., Ostrander EA., Cussenot O., Cancel-Tassin G., Hoegel J., Herkommer K., Schleutker J., Tammela TLJ., Rathinakannan V., Sipeky C., Wiklund F., Grönberg H., Aly M., Isaacs WB., Dickinson JL., FitzGerald LM., Chua MLK., Nguyen-Dumont T., PRACTICAL Consortium None., Schaid DJ., Southey MC., Eeles RA., Kote-Jarai Z.
BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.