差异表达基因microRNA结合位点遗传变异与中国人乳腺癌发病机制的研究

Breast Cancer ranked as a serious threat to women's health is one of the most common cancer in females. The differentially expressed genes of tumor and normal tissues play an important role in the occuring and development of the breast cancer. MicroRNA participates in the cell proliferation, differentiation, apoptosis and a series of physiological processes. The single nucleotide polymorphisms(SNPs) located in the miRNA binding sites' 3' untranslated region may affect the genes' expression by changing the combination between miRNA and the differentially expressed genes, and then be related to the individuals' tumor susceptibility. Our group has found the 7 (including BRCA1、BCAH1、KRAS and so on) most significant difference genes which were differentially expressed in breast cancer through the databases. We have also completed the genotying of the eight SNPs which meet the certain frequency standards and located in the 3' untranslated region of these differentially expressed genes and then initially obtained 2 SNPs that may be related to the breast cancer susceptibility. This study intends to continue to carry out a large sample size case-control study to verify these two SNPs and conduct a series of biochemistry and molecular biology experiments to research the biological functions of these genetic variations, then provide evidences to explore the molecular mechanisms of breast cancer development and the factors that affect breast cancer prognosis.

乳腺癌是严重威胁女性健康的最常见肿瘤之一，肿瘤组织与正常组织差异表达基因在肿瘤的发生发展中起重要作用。microRNA（miRNA）参与细胞增殖、分化、凋亡等一系列生理功能，位于miRNA结合位点3'非翻译区的单核苷酸多态（single nucleotide polymorphism, SNP）可能通过改变差异表达基因与miRNA的结合而影响基因表达，从而与个体的肿瘤易感性相关。本课题组已通过数据库挖掘出乳腺癌中表达差异最显著的7个基因（包括BRCA1、BCAH1、KRAS等），并完成了对上述乳腺癌差异表达基因3'非翻译区中符合一定频率标准的8个SNP位点的基因分型，初步筛选出出2个与乳腺癌发病显著相关的SNP。本研究拟继续针对这两个SNP开展大样本量的病例-对照研究进行验证，并采用一系列生物化学和分子生物学实验，研究此遗传变异的生物学功能，进而为探索乳腺癌发生发展的分子机制和

三阴性乳腺癌是一类易于早期复发转移且高度异质性的乳腺癌亚型。本研究的主要目的是寻找与三阴性乳腺癌预后的相关的单核苷酸多态（SNP），为探索乳腺癌发生发展的分子机制和影响乳腺癌预后的因素提供依据。研究充分整合并利用生物信息学数据库“ensemble”、“NCBI”及“MirSNP”选择位于乳腺癌差异表达基因3′UTR的111个SNP作为候选位点。采用两阶段验证方法以323个三阴性乳腺癌患者为研究对象，就候选SNP进行关联研究，最终确定位于FABP4基因的rs1054135遗传变异与三阴性乳腺癌的复发转移显著相关，且通过多重检验（FDR<0.05）。与携带A等位基因的患者相比，携带GG基因型患者复发风险更低，且无复发生存期（DFS）更长，在总体样本中，HR达到0.269 [95%CI.0.098−0.735; P=0.001]。研究还发现，对于rs1054135AA/AG型患者，高BMI(BMI≥25kg/m2)可进一步提高复发风险(HR2.53; 95%CI 1.06–6.03)。随后对癌旁脂肪组织进行免疫组化染色，并利用光密度分析仪进行定量检测（IOD值），通过Mann-Whitney U检验发现FABP4表达水平在携带rs1054135 GG基因型及无复发生存患者中更低，P值分别为0.0004和0.0091。以上结果表明脂代谢相关基因FABP4及位于其3`UTR的SNP与三阴性乳腺癌预后相关，揭示可能影响三阴性乳腺癌复发转移的遗传学基础。相关研究成果可进行深入的分子生物学功能探索及临床前研究，并有望找到可用于指导临床上早期诊断的有效标志物及个体化治疗靶点。此外，研究再次验证体重指数与乳腺癌预后的相关性，特别是对于某些特定基因型的患者而言，体重及生活方式的干预对于改善疾病预后具有重要意义。

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