联合GWAS、eQTL及meQTL发掘宫颈癌新辅助化疗耐药标记物及机制研究

Prediction of response to neoadjuvant chemotherapy (NACT) of cervical cancer is the key to improve the effect of neoadjuvant chemotherapy, however there is no good predict marker in clinic. In our previous genome-wide association study (GWAS) of response to NACT, we found four SNPs associated with response to NACT. However, predicting the response use only SNPs did not have high accuracy, and the molecular mechanism how the SNPs effect the response to NACT is difficult to explain. Studies have shown that SNP likely to affect clinical traits by influencing the expression of gene expression (eQTL) and DNA methylation (meQTL). In preliminary experiment, the methylation of CDH13, which one of the four SNPs is located, was correlated with the response to NACT. In this study, we aim to explore the mechanism by which the SNPs affect the response to neoadjuvant chemotherapy of cervical cancer by detecting the gene expression and DNA methylation near these four SNPs using the GWAS, eQTL analysis and meQTL analysis. Our study will provide new candidate genes and clinical biomarkers for the researches of response to neoadjuvant chemotherapy.

宫颈癌新辅助化疗（neoadjuvant chemotherapy, NACT）敏感性预测是提高新辅助化疗疗效的关键和难点，而临床上并没有较好的NACT疗效预测指标。我们前期通过宫颈癌NACT敏感性全基因组关联分析（GWAS），发现了4个NACT敏感性相关单核苷酸多态性（SNP）位点。研究表明SNP可能通过影响周围基因表达量或者DNA甲基化状态从而影响临床性状。然而单纯的SNP分析并不能较好的预测宫颈癌新辅助化疗的疗效，SNP影响宫颈癌新辅助化疗疗效的分子机制也很难解释。本项目拟通过检测NACT敏感性相关的4个SNP位点附近基因表达情况及DNA甲基化水平，联合GWAS、eQTL分析及meQTL分析等方法，构建较完整的SNP—基因表达/DNA甲基化—新辅助化疗敏感性关系图。挖掘SNP影响宫颈癌NACT敏感性的遗传学基础，为宫颈癌新辅助化疗敏感性研究提供新的候选基因和临床标记物。

宫颈癌新辅助化疗（Neoadjuvant chemotherapy, NACT）敏感性预测可以帮助临床上新辅助化疗应用的决策。前期我们通过全基因组关联分析（GWAS）项目找到了几个新辅助化疗疗效相关的SNP位点。在本项目中，我们纳入了新的宫颈癌新辅助化疗的患者，采集了患者的临床病理资料和血液标本。我们发现四个新辅助化疗疗效相关SNP中的三个（rs6812281，rs4590782，rs1364121）为新辅助化疗疗效的独立预测因素。然而SNP附近基因表达量和DNA甲基化状态与新辅助化疗疗效无统计学差异。我们发现三个疗效显著相关的SNP位点联合宫颈癌临床指标SCCAg可以将患者分成疗效差异更大的亚组。我们同时发现rs4590782分型结合化疗后SCCAg水平能将患者分成具有显著差异的总生存和无瘤生存的四个亚组。部分研究表明SNP分型会影响肿瘤微环境，因此我们将在后续研究中，继续探索SNP分型与免疫微环境影响宫颈癌新辅助化疗疗效的机制。