摘要目的 探讨DNA双链断裂修复基因XRCC2和XRCC5基因多态性与肺癌肿瘤细胞对铂类药物化疗敏感性的关系.方法 对150例手术肺癌患者应用MTT法检测肿瘤细胞对铂类药物的敏感性,并应用聚合酶链反应-限制性片段长度多态性和限制性内切酶分析-聚合酶链反应方法 检测XRCC2、XRCC5多态性,分析基因多态性对化疗药物敏感性的影响.结果 肿瘤组织对卡铂(CBP)和顺铂(DDP)的敏感率,XRCC2、C41657T T等位基因(C/T+T/T基因型)者为70.2%和66.7%,显著高于C/C基因型者的53.7%(χ2=3.97,P=0.046)和49.5%(χ2=4.25,P=0.039),T等位基因(C/T+T/T基因型)个体的肿瘤组织对CBP和DDP敏感性是C/C基因型者的2.06倍(经病理类型校正后的OR值为2.06,95%CI为1.02～4.18)和2.07倍(经病理类型校正后的OR值为2.07,95%CI为1.04～4.14).XRCC2 G4234C C等位基因(G/C+C/C)和G/G基因型个体的肿瘤组织对CBP和DDP耐药组和敏感组之间的基因型分布差异无统计学意义(CBP组χ2=0.09,P=0.766;DDP组χ2=1.63,P=0.202).XRCC2 4种单倍体型分布在对CBP耐药组与敏感组之间,差异无统计学意义(P>0.05).而在DDP耐药组与敏感组之间差异有统计学意义(χ2=9.60,P=0.022),41657T/4234G单倍体型患者的肿瘤组织对DDP敏感性是携带41657C/4234G单倍体型患者的2.18倍(OR=2.18,95%CI为1.15～4.12).肿瘤组织对CBP和DDP的敏感率,XRCC5 G74582A G等位基因(A/G+G/G基因型为57.9%和61.8%,A/A基因型为62.2%和50.0%,耐药组和敏感组之间的基因型分布差异无统计学意义(CBP组χ2=0.28,P=0.594;DDP组χ2=2.13,P=0.144),XRCC5C74468A A等位基因(A/C+A/A)者为52.9%和62.7%,XRCC5 C74468A C/C基因型者为63.6%和52.5%,耐药组和敏感组之间的基因型分布差异无统计学意义(CBP组χ2=1.60,P=0.205;DDP组χ2=1.43,P=0.231).结论 XRCC2 C41657T SNP与患者肿瘤组织对CBP和DDP的敏感性相关.与41657C/4234G单体型相比,41657T/4234G单体型可显著增加肿瘤细胞对DDP的敏感性.XRCC5G74582A、C74468A SNP与患者肿瘤组织对CBP、DDP的敏感性之间无相关性.

abstractsObjective To study the associations between XRCC2 and XRCC5 single nucleotide polymorphisms (SNPs) and chemosensitivity of human lung cancer cells. Methods Specimens of human lung cancer were collected from 150 patients, 120 males and 30 females, aged 58. 1, during operation. MTT method was used to detect the sensitivity of the lung cancer cells to cisplatin (DDP) and carboplatin (CBP), and the patients were genotyped for polymorphisms in XRCC2 and XRCC5 genes. The polymorphisms of XRCC2 41657T C41657T and XRCC5 G74582A were detected by polymerase chain reaction-restriction fraction length polymorphism (PCR-RFLP), and the polymorphisms of XRCC2 G4234C and XRCC5 C74468A were detected by primer- introduced restriction analysis- polymerase chain reaction (PIRA-PCR). The correlation of these polymorphisms of these polymorphisms with the drug-sensitivity of lung cancer cells was analyzed. Results The sensitive rates of the lung cancer cells to CBP and DDP in the patients with XRCC2 41657T allele (C/T+T/T genotype) were 70.2% and 66.7% respectively, both significantly higher the those in the patients with C/C genotype [53.7% (χ2 = 3.97, P = 0.046) and 49.5% (χ2 =4.25 ,P=0.039) respectively]. The sensitivity levels to CBP and DDP in the patients with at least one T allele was 2. 06 times (pathological type adjusted OR = 2.06,95% CI = 1.02 - 4. 18) and 2.07 times (pathological type adjusted OR = 2. 07,95% CI = 1.04 - 4.14) higher than those in the patients with C/C genotype. There was no significant difference in the distribution of genotypes of XRCC2 G4234C C allele (C/C + G/C) and G/C genotype between the sensitive group and resistant groups (χ2 = 0.09, P = 0.766 for CBP and χ2 = 1.63, P = 0.202 for DDP). The sensitivity rate to DDP of the patients with 41657T/4234G haplotype was 2.28 times as high as that of the patients with 41657T/4234C (OR = 2.18, 95% CI = 1.15 -4.12). The sensitivity rates to CBP and DDP of the tumor tissues from the patients with the XRCC5 G74582A G allele (A/G + G/G), were 57.9% and 61.8% respectively, and those of the patients with the A/A genotype were 62.2% and 50.0% respectively. There was no significant differences in the genotype distribution between the sensitive and resistant groups (χ2 = 0.28, P = 0.594 for CBP, and χ2 = 2.13, P = 0.144 for and DDP). Conclusion The XRCC2 C41657T SNP is associated with the sensitivity to CBP and DDP. The sensitive rate to the drugs of the cancer cells with the combination of C/T + T/T genotype is higher than that with C/C genotype. In the subject with 41657T/4234G the sensitivity to the drugs of the cancer cells is higher than that with 41657C/4234G haplotypes. The XRCC5 G74582A and C74468A SNPs are not associated with the sensitivity to CBP and DDP.