CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer

Maren Weischer, Børge G. Nordestgaard, Paul D P Pharoah, Manjeet K. Bolla, Heli Nevanlinna, Laura J. Van't Veer, Montserrat Garcia-Closas, John L. Hopper, Per Hall, Irene L Andrulis, Peter Devilee, Peter A. Fasching, Hoda Anton-Culver, Diether Lambrechts, Maartje J Hooning, Angela Cox, Graham G. Giles, Barbara Burwinkel, Annika Lindblom, Fergus J CouchArto Mannermaa, Grethe Grenaker Alnæs, Esther M. John, Thilo Dörk, Henrik Flyger, Alison M Dunning, Qin Wang, Taru A. Muranen, Richard Van Hien, Jonine D Figueroa, Melissa C. Southey, Kamila Czene, Julia A Knight, Rob A.E.M. Tollenaar, Matthias W. Beckmann, Argyrios Ziogas, Marie Rose Christiaens, Johanna Margriet Collée, Malcolm W R Reed, Gianluca Severi, Frederik Marme, Sara Margolin, Janet E Olson, Veli-Matti Kosma, Vessela N. Kristensen, Alexander Miron, Natalia Bogdanova, Mitul Shah, Carl Blomqvist, Annegien Broeks, Mark E Sherman, Kelly Anne Phillips, Jingmei Li, Jianjun Liu, Gord Glendon, Caroline Seynaeve, Arif B Ekici, Karin Leunen, Mieke Kriege, Simon S Cross, Laura Baglietto, Christof Sohn, Xianshu Wang, Vesa Kataja, Anne Lise Børresen-Dale, Andreas Meyer, Douglas F Easton, Marjanka K. Schmidt, Stig E Bojesen

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Abstract

Purpose: We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and Methods: From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. Results: CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. Conclusion: Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Original languageEnglish
Pages (from-to)4308-4316
Number of pages9
JournalJournal of Clinical Oncology
Volume30
Issue number35
DOIs
Publication statusPublished - 10 Dec 2012
Externally publishedYes

Cite this

Weischer, M., Nordestgaard, B. G., Pharoah, P. D. P., Bolla, M. K., Nevanlinna, H., Van't Veer, L. J., Garcia-Closas, M., Hopper, J. L., Hall, P., Andrulis, I. L., Devilee, P., Fasching, P. A., Anton-Culver, H., Lambrechts, D., Hooning, M. J., Cox, A., Giles, G. G., Burwinkel, B., Lindblom, A., ... Bojesen, S. E. (2012). CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. Journal of Clinical Oncology, 30(35), 4308-4316. https://doi.org/10.1200/JCO.2012.42.7336