Abstract
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.
Highlights
To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer
ESR1 polymorphisms and breast cancer susceptibility The distributions of demographic characteristics and major risk factors for breast cancer were comparable in the cases and controls (Supplementary Table S1)
To determine the breast tumorigenic contribution of ESR1, we examined whether the genotypic and allelic distribution of the gene differed between the 940 cases and 1,547 controls (921 cases and 1,533 controls had results of complete 15 single-nucleotide polymorphisms (SNP))
Summary
A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. 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. Study subjects This case-control study is part of an ongoing cooperative study aimed at understanding the causes of breast cancer in Taiwan, which is characterized by low incidence, early tumor onset, hormone dependency, and novel genomic alterations [28,29,30]. The characteristics of these study participants have already been described in detail [29, 31, 32]. Considerations regarding methodologic issues in the present study (such as study design, sampling scheme, and potential bias) have been described in detail [29, 31, 32]
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