目的 探讨DNA聚合酶ζ亚基REV3基因单核苷酸多态性(SNPs)与卵巢癌对铂类药物化疗敏感性的关系.方法 收集本院2013年1月至2016年12月接受含铂类化疗方案112例卵巢癌患者的外周静脉血,根据最小等位基因频率 MAF>O.1和连锁不平衡参数 r2>0.8的原则筛选 REV3基因的6个 TagSNPs(rs181294、rs240966、rs4945880、rs465646、 rs3218573和rs462779),采用MassARRAY-IPLEX技术和基质辅助激光解吸电离飞行时间质谱平台(MALDI-TOF-MS)进行 REV3基因SNPs位点的基因分型,同时收集同期121例健康体检者的外周血作对照.采用Hardy-Weinberg平衡分析遗传平衡情况,比较两组以上SNPs位点的基因型和等位基因的分布差异并计算比值比(OR)来评价卵巢癌易感性;根据化疗效果将卵巢癌患者分为化疗敏感组和不敏感组,进一步分析REV3基因SNPS与卵巢癌对铂类药物化疗敏感性的关系.结果 112例卵巢癌患者和121例健康体检者REV3的6个TagSNPs均处于Hardy-Weinberg平衡状态.REV3 rs240966、rs4945880和 rs3218573基因型及等位基因分布在卵巢癌组与对照组中的差异无统计学意义且与卵巢癌易感性无关(P>0.05).卵巢癌组中携带REV3 rs181294、rs465646和rs462779最小等位基因频率分别为40.6％、46.0％和49.6％,均高于对照组的27.7％、和37.2％(P<0.05),且卵巢癌的发病风险分别升高至1.787、2.419和1.659倍.112例卵巢癌患者均可评价疗效,其中敏感59例,不敏感53例.进一步分析发现rs240966、rs4945880、rs3218573及rs462779基因型和等位基因分布与卵巢癌对铂类药物化疗敏感性无关,而与rs181294、rs465646基因型和等位基因分布有关,其中携带rs181294 A等位基因或rs465646 G等位基因者的含铂方案不敏感发生风险升高(P<0.05).结论 REV3 rs181294、rs465646与卵巢癌易感性及含铂方案敏感性有关,其中携带rsl81294 A或rs465646 G的人群卵巢癌易感性及含铂耐药的发生风险升高,为卵巢癌易感人群的筛查有一定价值.%Objective To investigate the single nucleotide polymorphisms (SNPs) of DNA polymerase ζ subunit REV3 gene and their sensitivity to platinum based chemotherapy in ovarian cancer. Methods The peripheral venous blood samples from 112 patients with ovarian cancer from January 2013 to December 2016 in our hospital were collected. According to the principle of minor allele frequency MAF>0.1 and linkage disequilibrium parameter r2>0.8,we screened 6 TagSNPs of REV3 gene (rsl81294,rs240966, rs4945880, rs465646, rs3218573 and rs462779). MassARRAY-IPLEX and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) were used to genotype the SNPs loci of the REV3 gene. Meanwhile, the peripheral blood samples of 121 health examiners at the same period were collected as control. Genetic balance was analyzed by Hardy-Weinberg balance. The distribution of genotypes and alleles of SNPs loci in both groups were compared and the odds ratio (OR) was used to evaluate the susceptibility of ovarian cancer. According to response of chemotherapy,ovarian cancer patients were divided into chemotherapy sensitive group and insensitive group,and we further analyzed the relationship between SNPs of REV3 gene and sensitivity of ovarian cancer to platinum-based chemotherapy. Results The 6 TagSNPs of REV3 in 112 ovarian cancer patients and 121 health examiners were in1 450000郑州大学第一附属医院妇科 the state of Hardy-Weinberg balance. There was no significant difference in genotype and allele distribution of REV3 rs240966, rs4945880 and rs3218573 between the ovarian cancer group and the control group, and it was not related to the susceptibility of ovarian cancer (P>0.05). In the ovarian cancer group, the minor allele frequencies of REV3 rs181294, rs465646 and rs462779 were 40.6％,46％ and 49.6％, higher than those in the control group 27.7％, 26.0％ and 37.2％ (P<0.05),and the risk of ovarian cancer increased to 1.787,2.419 and 1.659 folds in comparison with the control group. All ovarian cancer patients can evaluate the effect, of which 59 cases are sensitive,and 53 cases are insensitive. Further analysis showed that the sensitivity of ovarian cancer to platinum drugs were independent with genotype and allele distribution of rs240966, rs4945880, rs3218573 and rs462779, but related to the distribution of rsl81294 and rs465646 genotypes and alleles. In those with rsl81294 A allele or rs465646 G allele, the risk of insensitivity to platinum-based regiems was increased (P<0.05). Conclusion REV3 rs181294 and rs465646 are associated with susceptibility to ovarian cancer and sensitivity to platinum based regimens. The rs181294 A or rs465646 G is associated with increased risk of ovarian cancer and increased platinum resistance,which is valuable for screening ovarian cancer susceptible populations.
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