Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan.
Clin Cancer Res. 2010 Jul 1;16(13):3473-84. doi: 10.1158/1078-0432.CCR-09-3092. Epub 2010 Jun 22.
To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor alpha (ERalpha), are associated with susceptibility, clinical phenotype, and progression of breast cancer.
A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1-8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression.
SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction <0.05). One of these intron 1 SNPs was also significantly associated with low ERalpha expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer-specific survival rate of patients, but had opposite effects in ERalpha-negative and ERalpha-positive early-stage patients.
Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERalpha in these two populations.
检验雌激素受体α（ERα）基因 ESR1 多态性与乳腺癌易感性、临床表型和进展相关的假说。
对 940 例新发乳腺癌患者和 1547 例健康女性对照进行病例对照研究。选择位于 chr6:152,170,379-152,466,100（ESR1 基因外显子 1-8，不包括侧翼序列）的 15 个单核苷酸多态性（SNP），反映该基因的主要多态性，进行基因分型。比较病例和对照之间 SNP 的频率，以确定与癌症易感性相关的 SNP，以及不同临床表型的病例之间的 SNP，以确定 ESR1 多态性在癌症进展中的作用。
位于内含子 1 中的一个 SNP 簇和一个单倍型的 SNP 与乳腺癌易感性显著相关。这些内含子 1 SNP 与生殖危险因素的联合作用对肿瘤发生的贡献更为明显（交互作用 P<0.05）。这些内含子 1 SNP 之一也与肿瘤中 ERα 表达降低显著相关。有趣的是，相同的内含子 1 SNP 与较差的临床表型相关，包括肿瘤细胞的低分化和晚期。这些内含子 1 SNP 也与患者 5 年乳腺癌特异性生存率显著相关，但在 ERα 阴性和 ERα 阳性早期患者中具有相反的影响。
我们的研究结果为 ESR1 多态性在不同阶段乳腺癌易感性中的作用提供了支持。本研究中在中国女性中确定的重要 ESR1 SNP 与在西方乳腺癌女性中确定的 SNP 存在差异，提示 ERα 在这两个人群中的作用不同。
