Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cancer Res. 2011 Jun 1;71(11):3881-8. doi: 10.1158/0008-5472.CAN-10-2653. Epub 2011 May 24.
Estrogen metabolism and growth factor signaling pathway genes play key roles in breast cancer development. We evaluated associations between breast cancer and tagging single-nucleotide polymorphisms (SNP) of 107 candidate genes of these pathways using single allele- and haplotype-based tests. We first sought concordance of associations between two study populations: the Nashville Breast Cohort (NBC; 510 cases, 988 controls), and the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer study (1,145 cases, 1,142 controls). Findings across the two study populations were concordant at tagging SNPs of six genes, and at previously published SNPs of FGFR2. We sought further replication of results for EGFR, NCOA7, and FGFR2 in the independent Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls). Associations at NCOA7 and FGFR2 replicated across all three studies. The association at NCOA7 on 6q22.32, detected by a haplotype spanning the initial protein-coding exon (5'-rs9375411, rs11967627, rs549438, rs529858, rs490361, rs17708107-3'), has not been previously reported. The haplotype had a significant inverse association with breast cancer in each study [OR(Het): 0.69 (NBC), 0.76 (CGEMS), 0.79 (CBCS)], and a meta-analysis OR(Het) of 0.75 (95% CI, 0.65-0.87, P = 1.4 × 10(-4)) in the combined study populations. The haplotype frequency was 0.07 among cases, and 0.09 among controls; homozygotes were infrequent and each OR(Hom) was not significant. NCOA7 encodes a nuclear receptor coactivator that interacts with estrogen receptor α to modulate its activity. These observations provide consistent evidence that genetic variants at the NCOA7 locus may confer a reduced risk of breast cancer.
雌激素代谢和生长因子信号通路基因在乳腺癌的发展中起着关键作用。我们使用基于单等位基因和单倍型的测试，评估了这些通路的 107 个候选基因的标记单核苷酸多态性 (SNP) 与乳腺癌之间的关联。我们首先寻求两个研究人群之间关联的一致性：纳什维尔乳腺癌队列 (NBC；510 例病例，988 例对照) 和癌症遗传易感性标记物 (CGEMS) 乳腺癌研究 (1145 例病例，1142 例对照)。在这两个研究人群中，六个基因的标记 SNP 和先前发表的 FGFR2 SNP 的结果是一致的。我们在独立的协作乳腺癌研究 (CBCS；1552 例病例，1185 例对照) 中进一步复制了 EGFR、NCOA7 和 FGFR2 的结果。NCOA7 和 FGFR2 的关联在所有三项研究中均得到复制。在 6q22.32 上的 NCOA7 关联，通过跨越初始蛋白编码外显子的单倍型检测到 (5'-rs9375411、rs11967627、rs549438、rs529858、rs490361、rs17708107-3')，以前没有报道过。在每个研究中，该单倍型与乳腺癌均呈显著负相关 [OR(Het)：0.69 (NBC)、0.76 (CGEMS)、0.79 (CBCS)]，在联合研究人群中的荟萃分析 OR(Het) 为 0.75 (95%CI，0.65-0.87，P = 1.4×10(-4))。在病例中，该单倍型的频率为 0.07，在对照中为 0.09；纯合子很少见，每个 OR(Hom)均不显著。NCOA7 编码一种核受体共激活因子，与雌激素受体 α 相互作用以调节其活性。这些观察结果提供了一致的证据，表明 NCOA7 基因座的遗传变异可能降低乳腺癌的风险。
