Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.
Schmidt MK., Hogervorst F., van Hien R., Cornelissen S., Broeks A., Adank MA., Meijers H., Waisfisz Q., Hollestelle A., Schutte M., van den Ouweland A., Hooning M., Andrulis IL., Anton-Culver H., Antonenkova NN., Antoniou AC., Arndt V., Bermisheva M., Bogdanova NV., Bolla MK., Brauch H., Brenner H., Brüning T., Burwinkel B., Chang-Claude J., Chenevix-Trench G., Couch FJ., Cox A., Cross SS., Czene K., Dunning AM., Fasching PA., Figueroa J., Fletcher O., Flyger H., Galle E., García-Closas M., Giles GG., Haeberle L., Hall P., Hillemanns P., Hopper JL., Jakubowska A., John EM., Jones M., Khusnutdinova E., Knight JA., Kosma V-M., Kristensen V., Lee A., Lindblom A., Lubinski J., Mannermaa A., Margolin S., Meindl A., Milne RL., Muranen TA., Newcomb PA., Offit K., Park-Simon T-W., Peto J., Pharoah PDP., Robson M., Rudolph A., Sawyer EJ., Schmutzler RK., Seynaeve C., Soens J., Southey MC., Spurdle AB., Surowy H., Swerdlow A., Tollenaar RAEM., Tomlinson I., Trentham-Dietz A., Vachon C., Wang Q., Whittemore AS., Ziogas A., van der Kolk L., Nevanlinna H., Dörk T., Bojesen S., Easton DF.
PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. CONCLUSION: These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.