染色体6q25.1区域多态性与乳腺癌遗传易感性的关系及功能研究

Breast cancer is a complex polygenic disorder for which genetic factors play a significant role in disease etiology. We recently identified a novel single nucleotide polymorphism (SNP) rs2046210 for breast cancer risk in a genome-wide association study (GWAS) conducted among Asians. SNP rs2046210 is located at chromsome 6q25.1 region, with 15kb upstream of estrogen receptor α (ESR1) and 6kb downstream of unknown gene C6orf97. We found in previous work that rs2046210 mutant genotype was associated with high expression of gene ESR1 and C6orf97 in breast tumor tissues. These two genes were positively correlated in breast tumor tissues and are associated with estrogen metabolism. ERα is an important target for the endocrine treatment of breast cancer, suggesting this susceptibility region and unknown gene C6orf97 are very important and may become a potential target for breast cancer detection and therapy. This study focus on fine-mapping of the breast cancer susceptibility region 6q25.1 in a large population, and interaction analysis with the environmental factors, and functional exploration for significant SNPs in this region and unknown gene C6orf97. It's facilitate to clarify the breast cancer etiology and pathogenesis, and screening of susceptible populations. More importantly, the significent findings of this study may provide a clude to breast cancer early diagnosis and individual prevention measures.

乳腺癌是复杂的多基因疾病，遗传因素发挥了重要作用。我们参与的乳腺癌GWAS研究发现多态位点SNP rs2046210与亚洲女性乳腺癌的患病风险相关。该位点位于染色体6q25.1区域,雌激素受体α（ESR1）基因上游15kb，未知基因C6orf97的下游。前期工作中发现rs2046210突变基因型与乳腺癌组织中ESR1和C6orf97基因的高表达密切相关，同时这两个基因的表达呈正相关。ERα是乳腺癌内分泌治疗的重要靶点，提示我们此易感区域和未知基因C6orf97非常重要，可能成为潜在的乳腺癌的检测和治疗靶点。本研究着重于将大样本人群作为研究对象对乳腺癌GWAS结果6q25.1区域，进行精细作图，与环境因素的交互作用分析，并对此易感区域SNPs和C6orf97进行功能探索，为阐明乳腺癌的病因及其发生机制，筛选易感人群，开展早期诊断及实施对象明确的个体预防措施提供基础，具有深远的临床意义。

乳腺癌是女性发病、死亡第一位恶性肿瘤。GWAS研究发现SNP rs2046210 与亚洲女性乳腺癌的患病风险相关。本研究探讨染色体6q25.1区域SNP的乳腺癌易感位点及功能研究。结果显示对6q25.1区域的SNP精细作图发现此区域存在Haplotype，与乳腺癌的发病风险高度相关，并影响乳腺癌的骨转移率。6q25.1区域多个SNP位点不同基因型与ERα和C6orf97表达高度相关，为进一步揭示乳腺癌发病原因提供线索。3’UTR区SNP，通过miRNA预测、空间结构自由能计算和Luciferase assay证实miR-150与C6orf97 3′UTR结合，同时rs6932260位点多态性影响此结合过程。mRNA和蛋白水平结果显示，miRNA-150共调节C6orf97和ESR1的表达。在非基因区域SNP，通过Luciferase assay发现具有潜在enhancer功能的SNP区域；在外显子区域SNP，通过细胞生长曲线和Transwell等实验证实SNP对乳腺癌细胞生长和迁移能力的影响。C6orf97和ESR1在乳腺癌组织中表达呈正相关。利用生物信息学和结构生物学方法对C6orf97蛋白结构进行预测，揭示ESR与C6orf97蛋白之间存在相互作用位点，Co-IP 实验证实C6orf97与ER结合。因此，本研究提示我们6q25.1区域易感位点和这个C6orf97未知基因非常重要，可能成为潜在的乳腺癌的检测和治疗靶点。