ERCC1的多态性与肺癌化疗耐药性及毒副作用的关联研究以及meta分析

【作者】 钟逾；

【导师】 卢大儒；

【作者基本信息】 复旦大学 ， 遗传学， 2008， 硕士

【摘要】 第一部分ERCC1基因的多态性和肺癌的铂类药物化疗疗效及毒副作用的关联研究肺癌是肿瘤治疗中的难点之一,肺癌患者的总生存率较低。其中化疗的有效率仅为18-40%,而影响化疗疗效的主要原因之一是耐药性,其中又以铂类耐药占重要地位,铂类药物的药理作用就是通过引起DNA交联或形成DNA加合物,抑制DNA复制而杀死肿瘤细胞。而细胞中的NER修复通路则有可能降低铂类的疗效。其中ERCC1是NER通路中的主效基因,通过与XPF组成复合体的形式负责5’的核苷酸切除,它的上调表达提高DRC,明显降低以铂类药物为基础的化疗疗效。该基因的T19007C位点是研究得较热门的一个SNP位点,我们采用Massarray对样本中的209名NSCLC患者的该位点进行了分型,并进行统计分析。在对该位点和疗效的关联分析中,任何遗传模型下均未显示两者之间的关联。在对化疗毒副作用作用的关联分析中,发现显性遗传模型下该位点与肠胃毒副作用存在关联。（TT+CT vs CC,P=0.047,优势比（OR）=3.311,95%置信区间（CI）:1.015～10.796）。本部分研究分析了ERCC1的较热门的SNP位点与化疗疗效及毒副作用的统计学关系。研究结果可作为下一步扩大样本量并在不同药物中开展的关联分析提供依据。第二部分ERCC1基因T19007C（rs11615）的多态性和铂类药物化疗疗效的meta-分析ERCC1（错配切除交叉互补修复酶）是NER修复复合物中的一个功能单位,行使DNA链的5’切除修复。另外,所选取的T19007C位点为同义突变位点,不涉及氨基酸的改变,但有可能影响密码子利用效率,从而对疗效发挥影响。以往对ERCC1 T19007C及化疗疗效所进行的关联分析结果存在冲突。我们在此对所有的合格单项研究汇总进行meta-分析。总体来说,T19007等位基因突变（555份有效组病例和595份无效组病例）并不表现出对化疗的显著耐药性。(P=0.732,优势比（OR）=0.950;95%置信区间（CI）:0.707-1.276,P_异质性=0.017)。在所有遗传模型下进行的meta-分析也未显示出显著的与疗效的关联。而单项研究间存在异质性。需要对更大的人群样本进行更进一步的研究,以更加清晰地阐明ERCC1的T19007C位点在不同癌中的地位和作用。更多还原

【Abstract】 PartⅠThe association study of ERCC1 polymorphism and chemotherapy response/toxicity of lung cancerThe survival rate of lung-cancer patients still remained low.The response rate of chemotherapy is about 18-40%,the factor which affects the chemotherapy response is drug resistance,especially platinum drug.The drug mechanism is that DNA adducts was formed to kill tumor cells.And the NER pathway may greatly reduced the effects of platinum drugs.ERCC1 is one of the maineffect genes of NER,excising nucleotide by forming complex with XPF.Its up-regulating increases DRC,and obviousely reduces chemotherapy response.The T19007C site is a "hot spot" SNP,which was genotyped with Massarray.No association was found under any genetic model in the study on chemotherapy response,in this study including 209 NSCLC patients.We found this SNP was associated with gastrointestinal toxicity only under recessive genetic model（TT+CT vs CC）.（P=0.047,odds ratio（OR）=3.311;95%confidence interval（CI）:1.015～10.796）.In sum,this part specialized in one of the popular SNPs of ERCC1,and its statistic relationship of chemotherapy response and toxicity.The present results may supply clue for the further study based on larger sample treated with different drugs. PartⅡAmeta-analysis of ERCC1 T19007C（rs11615） and chemotherapy responseERCC1（excision repair cross complementation group 1） is a subunit of the nucleotide excision repair complex,which can perform DNA strand incision correction of DNA damage.Association studies on the ERCC1 polymorphisms（T19007C） in platinum-based chemotherapy of cancer had shown conflicting results.We performed a meta-analysis from all eligible studies to assess the purported associations.Overall,the T19007 allele（555 responders and 595 non-responders） showed no significant effect on chemotherapy resistance compared to 19007C allele(P=0.732,odds ratio（OR）=0.950;95%confidence interval（CI）:0.707-1.276, P_{heterogeneity}=0.017) in all subjects.Meta-analysis under any genetic contrasts did not reveal significant association of T19007C to drug resistance of chemotherapy in all subjects.Significant between-study heterogeneity existed in T19007C.More studies based on larger population should be required to further evaluate the role of ERCC1 T19007C polymorphisms in different cancer.更多还原