Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers
Authors: Schmidt Marjanka K. , Hogervorst Frans , van Hien Richard , Cornelissen Sten , Broeks Annegien , Adank Muriel A. , Meijers Hanne , Waisfisz Quinten , Hollestelle Antoinette , Schutte Mieke , van den Ouweland Ans , Hooning Maartje , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Antoniou Antonis C. , Arndt Volker , Bermisheva Marina , Bogdanova Natalia V. , Bolla Manjeet K. , Brauch Hiltrud , Brenner Hermann , Brüning Thomas , Burwinkel Barbara , Chang-Claude Jenny , Chenevix-Trench Georgia , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Dunning Alison M. , Fasching Peter A. , Figueroa Jonine , Fletcher Olivia , Flyger Henrik , Galle Eva , García-Closas Montserrat , Giles Graham G. , Haeberle Lothar , Hall Per , Hillemanns Peter , Hopper John L. , Jakubowska Anna , John Esther M. , Jones Michael , Khusnutdinova Elza , Knight Julia A. , Kosma Veli-Matti , Kristensen Vessela , Lee Andrew , Lindblom Annika , Lubinski Jan , Mannermaa Arto , Margolin Sara , Meindl Alfons , Milne Roger L. , Muranen Taru A. , Newcomb Polly A. , Offit Kenneth , Park-Simon Tjoung-Won , Peto Julian , Pharoah Paul D.P. , Robson Mark , Rudolph Anja , Sawyer Elinor J. , Schmutzler Rita K. , Seynaeve Caroline , Soens Julie , Southey Melissa C. , Spurdle Amanda B. , Surowy Harald , Swerdlow Anthony , Tollenaar Rob A.E.M. , Tomlinson Ian , Trentham-Dietz Amy , Vachon Celine , Wang Qin , Whittemore Alice S. , Ziogas Argyrios , van der Kolk Lizet , Nevanlinna Heli , Dörk Thilo , Bojesen Stig , Easton Douglas F. 
Published: June 2016

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.