TY - JOUR
T1 - Variants in the ATM gene associated with a reduced risk of contralateral breast cancer
AU - Concannon, Patrick
AU - Haile, Robert W.
AU - Bøorresen-Dale, Anne Lise
AU - Rosenstein, Barry S.
AU - Gatti, Richard A.
AU - Teraoka, Sharon N.
AU - Diep, Anh T.
AU - Jansen, Laila
AU - Atencio, David P.
AU - Langholz, Bryan
AU - Capanu, Marinela
AU - Liang, Xiaolin
AU - Begg, Colin B.
AU - Thomas, Duncan C.
AU - Bernstein, Leslie
AU - Olsen, Jørgen H.
AU - Malone, Kathleen E.
AU - Lynch, Charles F.
AU - Anton-Culver, Hoda
AU - Bernstein, Jonine L.
PY - 2008/8/15
Y1 - 2008/8/15
N2 - 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 serinethreonine 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.
AB - 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 serinethreonine 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.
UR - https://www.scopus.com/pages/publications/53049104973
U2 - 10.1158/0008-5472.CAN-08-0134
DO - 10.1158/0008-5472.CAN-08-0134
M3 - Article
C2 - 18701470
AN - SCOPUS:53049104973
SN - 0008-5472
VL - 68
SP - 6486
EP - 6491
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -