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Variants in the ATM Gene Associated with a Reduced Risk of Contralateral Breast Cancer

¹ Department of Biochemistry and Molecular Genetics and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia; ² Department of Preventive Medicine, University of Southern California, ³ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California; ⁴ Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre and Faculty of Medicine, University of Oslo, Oslo, Norway; ⁵ Department of Radiation Oncology, Mount Sinai School of Medicine, ⁶ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁷ Department of Cancer Etiology, City of Hope National Medical Center, Duarte, California; ⁸ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ⁹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; ¹⁰ Department of Epidemiology, University of Iowa, Iowa City, Iowa; and ¹¹ Department of Medicine, University of California, Irvine, Irvine, California

Requests for reprints: Patrick Concannon, Department of Biochemistry and Molecular Genetics, University of Virginia, P.O. Box 800733, Charlottesville, VA 22908-0733. Phone: 434-982-3288; Fax: 434-924-5069; E-mail: patcon{at}virginia.edu.

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3–0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3–0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1–0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1–0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53. [Cancer Res 2008;68(16):6486–91]