Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

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Marjanka K Schmidt, Frans Hogervorst, Richard R van Hien, Sten Cornelissen, Annegien Broeks, Muriel A Adank, Hanne Meijers-Heijboer, Quinten Waisfisz, Antoinette Hollestelle, Mieke Schutte, Ans van den Ouweland, Maartje Hooning, Irene L Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, Volker Arndt, Marina Bermisheva, Natalia V Bogdanova, Manjeet K Bolla & 64 others Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Jenny Chang-Claude, Georgia Chenevix-Trench, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Alison M Dunning, Peter A Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Eva Galle, Montserrat García-Closas, Graham Giles, Lothar Haeberle, Per Hall, Peter Hillemanns, John L Hopper, Anna Jakubowska, Esther M John, Michael Jones, Elza Khusnutdinova, Julia A Knight, Veli-Matti Kosma, Vessela Kristensen, Andrew Lee, Annika Lindblom, Jan Lubinski, Arto Mannermaa, Sara Margolin, Alfons Meindl, Roger L Milne, Taru A Muranen, Polly A Newcomb, Kenneth Offit, Tjoung-Won Park-Simon, Julian Peto, Paul P D Pharoah, Mark Robson, Anja Rudolph, Elinor J Sawyer, Rita K Schmutzler, Caroline Seynaeve, Julie Soens, Melissa C Southey, Amanda B Spurdle, Harald M Surowy, Anthony Swerdlow, Rob A E M Tollenaar, Ian Tomlinson, Amy Trentham-Dietz, Celine Vachon, Qin Wang, Alice S Whittemore, Argyrios Ziogas, Lizet van der Kolk, Heli Nevanlinna, Thilo Doerk, Stig Bojesen, Douglas F Easton

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.

Original languageEnglish
JournalJournal of Clinical Oncology
Volume34
Issue number23
Pages (from-to)2750-60
Number of pages11
ISSN0732-183X
DOIs
Publication statusPublished - 10 Aug 2016

    Research areas

  • Journal Article

ID: 176955144