Gold Bert, Kalush Francis, Bergeron Julie, Scott Kevin, Mitra Nandita, Wilson Kelly, Ellis Nathan, Huang Helen, Chen Michael, Lippert Ross, Halldorsson Bjarni V, Woodworth Beth, White Thomas, Clark Andrew G, Parl Fritz F, Broder Samuel, Dean Michael, Offit Kenneth
Human Genetics Section, Laboratory of Genomic Diversity, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Cancer Res. 2004 Dec 15;64(24):8891-900. doi: 10.1158/0008-5472.CAN-04-1256.
Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), approximately O.4; 95% confidence interval (CI), 0.2-0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2-3.8; P < 0.05). A unique risk haplotype was present in approximately 7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2-2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.
近八分之一的美国女性在其一生中会患乳腺癌。大多数乳腺癌与遗传性综合征无关，发生在绝经后女性中，且雌激素和孕激素受体呈阳性。雌激素暴露是乳腺癌的一个流行病学风险因素，而雌激素是一种强大的乳腺促有丝分裂原。我们研究了来自纽约市的615名健康受试者和1011名经组织学确诊为乳腺癌的个体中雌激素受体的单核苷酸多态性（SNP）。我们分析了孕激素受体基因（PGR）中的13个SNP、雌激素受体1基因（ESR1）中的17个SNP以及雌激素受体2基因（ESR2）中的8个SNP。我们在ESR1中观察到三种常见单倍型，它们与乳腺癌风险降低相关[比值比（OR），约为0.4；95%置信区间（CI），0.2 - 0.8；P < 0.01]。另一种单倍型与乳腺癌风险增加相关（OR，2.1；95% CI，1.2 - 3.8；P < 0.05）。在约7%的老年阿什肯纳兹犹太研究受试者中存在一种独特的风险单倍型（OR，1.7；95% CI，1.2 - 2.4；P < 0.003）。我们将ESR1风险单倍型缩小到启动子区域和第一个外显子。我们在阿什肯纳兹犹太人的ESR1和ESR2中定义了其他几种可能增加乳腺癌易感性的单倍型。相比之下，我们发现PGR的任何变体或单倍型与乳腺癌之间均无关联。对这些单倍型进行遗传流行病学研究复制和功能测定应该能够更好地理解类固醇受体基因变体与乳腺癌风险的作用。
