Thomas Gilles, Jacobs Kevin B, Kraft Peter, Yeager Meredith, Wacholder Sholom, Cox David G, Hankinson Susan E, Hutchinson Amy, Wang Zhaoming, Yu Kai, Chatterjee Nilanjan, Garcia-Closas Montserrat, Gonzalez-Bosquet Jesus, Prokunina-Olsson Ludmila, Orr Nick, Willett Walter C, Colditz Graham A, Ziegler Regina G, Berg Christine D, Buys Saundra S, McCarty Catherine A, Feigelson Heather Spencer, Calle Eugenia E, Thun Michael J, Diver Ryan, Prentice Ross, Jackson Rebecca, Kooperberg Charles, Chlebowski Rowan, Lissowska Jolanta, Peplonska Beata, Brinton Louise A, Sigurdson Alice, Doody Michele, Bhatti Parveen, Alexander Bruce H, Buring Julie, Lee I-Min, Vatten Lars J, Hveem Kristian, Kumle Merethe, Hayes Richard B, Tucker Margaret, Gerhard Daniela S, Fraumeni Joseph F, Hoover Robert N, Chanock Stephen J, Hunter David J
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Nat Genet. 2009 May;41(5):579-84. doi: 10.1038/ng.353. Epub 2009 Mar 29.
We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.
我们在癌症易感性基因标记(CGEMS)计划中,对9770例乳腺癌患者和10799例对照进行了三阶段全基因组关联研究(GWAS)。在第一阶段,我们对1145例浸润性乳腺癌患者和1142例对照中的528173个单核苷酸多态性(SNP)进行了基因分型。在第二阶段,我们分析了4547例患者和4434例对照中的24909个顶级SNP。在第三阶段,我们在4078例患者和5223例对照中研究了21个基因座。发现了两个新的达到全基因组显著性水平的基因座。位于1号染色体1p11.2上的一个着丝粒周围SNP(rs11249433;经调整的基因型检验P = 6.74×10⁻¹⁰,自由度为2)位于与NOTCH2和FCGR1B相邻的一个大的连锁不平衡区域内;该信号在雌激素受体阳性肿瘤中更强。位于14号染色体14q24.1上的另一个SNP(rs999737;P = 1.74×10⁻⁷)定位于RAD51L1,这是同源重组DNA修复途径中的一个基因。我们还证实了与2号染色体2q35、5号染色体5p12、5q11.2、8号染色体8q24、10号染色体10q26和16号染色体16q12.1上基因座的关联。