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中国癌症防治杂志

中国癌症防治杂志 ›› 2014, Vol. 6 ›› Issue (2): 127-132.doi: 10.3969/j.issn.1674-5671.2014.02.06

• 基础研究 • 上一篇    下一篇

以基因通路富集法探索上皮性卵巢癌多药耐药相关生物学通路及功能性SNP位点

  

  1. 广西医科大学附属肿瘤医院妇瘤科；广西医科大学研究生学院；广西肿瘤防治研究所实验研究部；广西医科大学医学科学实验中心
  • 出版日期:2014-06-25 发布日期:2014-07-08
  • 通讯作者: 尹富强 E-mail:yinfq@mail2.sysu.edu.cn
  • 基金资助:

    广西医学科学实验中心开放基金资助项目（KFJJ2011-15）

Using gene-set enrichment pathway analysis to identify signaling pathways and functional single nucleotide polymorphisms related to multi-drug resistance in epithelial ovarian cancer

  • Online:2014-06-25 Published:2014-07-08

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摘要： 目的 借助生物信息学工具探索上皮性卵巢癌多药耐药相关的生物学通路及SNP位点。方法 从基因表达综合数据库的GSE13813芯片数据中筛选出初次术后经铂类和紫杉醇类联合化疗的73例患者，其中22例为化疗耐药，51例为化疗敏感。采用PLINK软件进行等位基因关联检验分析，对差异表达的SNP位点 （P<0.05）采用WebGestalt在线工具和DAVID进行基因通路富集分析，并筛选与上皮性卵巢癌多药耐药相关的共同通路。利用SciMiner工具检索上皮性卵巢癌多药耐药研究相关基因，并用上述方法进行通路分析以交叉验证。最后对通路涉及的SNP及其连锁位点采用Snpfunc网站进行功能预计。结果 敏感组和耐药组共有4 978个差异表达的SNP位点。通路分析显示黏附分子、钙离子信号和ErbB 信号途径与上皮性卵巢癌多药耐药相关。其中ErbB 信号在文献挖掘通路分析中得到交叉验证。11个连锁SNP可通过异常剪接、编码非同义氨基酸等方式改变基因功能，从而影响通路在上皮性卵巢癌联合化疗中的作用。结论 通过基因通路富集方法找到3个与上皮性卵巢癌多药耐药相关的通路及一批可能影响通路的功能性SNP位点。检测这些位点有助于预测上皮性卵巢癌联合化疗的反应。

关键词: 卵巢肿瘤, 上皮性卵巢癌, 多药耐药, 单核苷酸多态性, SNP芯片, 基因通路富集分析

Abstract: Objective This bioinformatics study aimed to explore signaling pathways and functional single nucleotide polymorphisms （SNPs） related to multidrug resistance（MDR） in epithelial ovarian cancer. Methods Patients with ovarian cancer treated by platinum and paclitaxel after primary surgery were selected from the SNP array（GSE13813） in the Gene Expression Omnibus （GEO） dataset. PLINK software and allelic tests were applied to identify SNPs significantly related to MDR（P<0.05），which were further analyzed online using gene-set enrichment pathway analysis（GSEA） in WebGestalt and DAVID. SciMiner was used to search for all genes potentially related to MDR in patients with epithelial ovarian cancer，and the corresponding functional pathways were explored using WebGestalt and DAVID.Finally，the on-line software Snpfunc was used to predict functions of SNPs in MDR-related pathways as well as of their partners in linkage disequilibrium. Results GSEA of 4978 significant SNPs from 22 platinum-resistant and 51 platinum-sensitive patients identified cell adhesion molecules and calcium-and ErbB-dependent signaling pathways as being potentially related to MDR.Literature analysis supported the association between the ErbB signaling pathway and MDR.Function prediction suggested that 11 functional SNPs may modify gene function by causing aberrant splicing or amino acid substitutions，potentially affecting response to combination chemotherapy. Conclusion Using GSEA，we identified three possible MDR-related signaling pathways and 11 functional SNPs that may help predict responses to platinum-based combination chemotherapy for epithelian ovarian cancer. These findings should be confirmed in future studies.

Key words: Ovarian neoplasm, Epithelial ovarian cancer, Multidrug resistance, Single nucleotide polymorphism, SNP array；Gene-set enrichment analysis