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The CHEK2*1100delC Allelic Variant and Risk of Breast Cancer: Screening Results from the Breast Cancer Family Registry

¹ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center; ² Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York; ³ Molecular Genetics Program, Benaroya Research Institute at Virginia Mason; ⁴ Department of Immunology, University of Washington School of Medicine, Seattle, Washington; ⁵ Northern California Cancer Center, Fremont, California; ⁶ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; ⁷ Clinical and Genetic Epidemiology Research Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland; and ⁸ Stanford University School of Medicine, Department of Health Research and Policy, Stanford, California

Requests for reprints: Jonine L. Bernstein, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 3rd Floor, 307 East 63rd Street, New York, NY 10021. Phone: 646-735-8155; Fax: 646-735-0012. E-mail: bernstej{at}mskcc.org

CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.(Cancer Epidemiol Biomarkers Prev 2006;15(2):348–52)

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