Evaluation of functional genetic variants at 6q25.1 and risk of breast cancer in a Chinese population.

Yanru Wang,Juncheng Dai,Hongbing Shen,Zhenzhen Qin,Xiaoxiang Guan,Jiaping Chen,Zhibin Hu,Hongxia Ma,Guangfu Jin,Yisha He,Yue Jiang

doi:10.1186/s13058-014-0422-x

Yanru Wang, Juncheng Dai + Show 9 more

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https://doi.org/10.1186/s13058-014-0422-x

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Abstract

IntroductionSingle-nucleotide polymorphisms (SNPs) at 6q25.1 that are associated with breast cancer susceptibility have been identified in several genome-wide association studies (GWASs). However, the exact causal variants in this region have not been clarified.MethodsIn the present study, we genotyped six potentially functional single-nucleotide polymorphisms (SNPs) within the CCDC170 and ESR1 gene regions at 6q25.1 and accessed their associations with risk of breast cancer in a study of 1,064 cases and 1,073 cancer-free controls in Chinese women. The biological function of the risk variant was further evaluated by performing laboratory experiments.ResultsBreast cancer risk was significantly associated with three SNPs located at 6q25.1—rs9383935 in CCDC170 and rs2228480 and rs3798758 in ESR1—with variant allele attributed odds ratios (ORs) of 1.38 (95% confidence interval (CI): 1.20 to 1.57, P = 2.21 × 10-6), 0.84 (95% CI: 0.72 to 0.98, P = 0.025) and 1.19 (95% CI: 1.04 to 1.37, P = 0.013), respectively. The functional variant rs9383935 is in high linkage disequilibrium (LD) with GWAS-reported top-hit SNP (rs2046210), but only rs9383935 showed a strong independent effect in conditional regression analysis. The rs9383935 risk allele A showed decreased activity of reporter gene in both the MCF-7 and BT-474 breast cancer cell lines, which might be due to an altered binding capacity of miR-27a to the 3' untranslated region (3' UTR) sequence of CCDC170. Real-time quantitative reverse transcription PCR confirmed the correlation between rs9383935 genotypes and CCDC170 expression levels.ConclusionsThe results of this study suggest that the functional variant rs9383935, located at the 3' UTR of CCDC170, may be one candidate of the causal variants at 6q25.1 that modulate the risk of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0422-x) contains supplementary material, which is available to authorized users.

Highlights

Single-nucleotide polymorphisms (SNPs) at 6q25.1 that are associated with breast cancer susceptibility have been identified in several genome-wide association studies (GWASs)
Rs3983935 in Coiled-coil domain containing 170 (CCDC170) was selected because it is in strong linkage disequilibrium (LD) with rs2046210 (r2 = 0.86) and was predicted to (1) affect a potential binding site of microRNA-27a located in the 3′ untranslated region (3′ Untranslated region (UTR)) of CCDC170 and (2) regulate expression of CCDC170 in the expression quantitative trait loci (eQTL) analysis. Using another approach taking into consideration the existence of multiple independent breast cancer susceptibility loci at the 6q25.1 region and the importance of estrogen receptor 1 (ESR1) in breast cancer development, we focused on potential functional SNPs of ESR1
The breast cancer cases showed an earlier age at menarche, a later age at first live birth and a lower proportion of natural postmenopausal status compared with the controls

Summary

Introduction

Single-nucleotide polymorphisms (SNPs) at 6q25.1 that are associated with breast cancer susceptibility have been identified in several genome-wide association studies (GWASs). In recent genome-wide association studies (GWASs), researchers have identified numerous single-nucleotide polymorphisms (SNPs) associated with breast cancer risk in diverse populations [5]. Among these SNPs, rs2046210, located between coiled-coil domain containing 170 (CCDC170, called C6orf97) and estrogen receptor 1 (ESR1) at 6q25.1, was first reported to be associated with the risk of breast cancer in Chinese populations [6]. One intronic variant, rs3757318 in CCDC170 [7], and another intronic rs9383951 in ESR1 [8], were found to be associated with breast cancer risk. Investigators in numerous studies have confirmed these associations with breast cancer in this region, especially for rs2046210 [9,10,11,12]

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