Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers
Marjanka K Schmidt1, Frans Hogervorst1, Richard van Hien1
1Marjanka K. Schmidt, Frans Hogervorst, Richard van Hien, Sten Cornelissen, Annegien Broeks, and Lizet van der Kolk, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital; Muriel A. Adank, Hanne Meijers, and Quinten Waisfisz, VU University Medical Center, Amsterdam; Antoinette Hollestelle, Mieke Schutte, Maartje Hooning, and Caroline Seynaeve, Erasmus MC Cancer Institute; Ans van den Ouweland, Erasmus University Medical Center, Rotterdam; Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden, the Netherlands; Irene L. Andrulis and Julia A. Knight, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital; Irene L. Andrulis and Julia A. Knight, University of Toronto, Toronto, Ontario, Canada; Hoda Anton-Culver and Argyrios Ziogas, University of California, Irvine; Peter A. Fasching, David Geffen School of Medicine, University of California, Los Angeles; Esther M. John, Cancer Prevention Institute of California, Fremont; Esther M. John, Alice S. Whittemore, Stanford University School of Medicine, Stanford, CA; Natalia N. Antonenkova, N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus; Antonis C. Antoniou, Manjeet K. Bolla, Andrew Lee, Alison M. Dunning, Paul D.P. Pharoah, Qin Wang, and Douglas F. Easton, University of Cambridge, Cambridge; Angela Cox and Simon S. Cross, University of Sheffield, Sheffield; Olivia Fletcher, Michael Jones, and Anthony Swerdlow, The Institute of Cancer Research; Julian Peto, London School of Hygiene and Tropical Medicine; Elinor J. Sawyer, King's College London, London; Jonine Figueroa, University of Edinburgh Medical School, Edinburgh; Ian Tomlinson, University of Oxford, Oxford, United Kingdom; Volker Arndt, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude, Anja Rudolph, Harold Surowy, German Cancer Research Center; Barbara Burwinkel and Harald Surowy, University of Heidelberg, Heidelberg; Natalia V. Bogdanova, Peter Hillemanns, Tjoung-Won Park-Simon, and Thilo
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.
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