晚期非小细胞肺癌对铂类药物的化疗敏感性与p53和p73基因多态的关系

Association of the responsiveness of advanced non-small cell lung cancer to platinum-based chemotherapy with p53 and p73 polymorphisms

目的探讨细胞凋亡相关基因p53和p73的遗传多态，与晚期非小细胞肺癌（NSCLC）对铂类药物化疗敏感性的关系。方法以聚合酶链反应（PCR）-限制性片段长度多态性（RFLP）和突变扩增阻抑系统（ARMS）分析方法，对165例以顺铂（DDP）或卡铂（CBP）为主进行化疗的晚期NSCLC患者，进行p53第72密码子Arg→Pro多态，和p73第2外显子G4C14-A4T14多态的检测，2～3个疗程后进行效果评价。以非条件Logistic回归模型比较不同基因型与化疗疗效的关系。结果携带p53 72Pro等位基因患者的化疗敏感性，是携带p53 72Arg／Arg基因型患者的2、46倍（95％CI，1．11～5．45，P=0．026）；而携带至少1个p73突变等位基因（A4T14）的患者，其化疗敏感性是携带p73 G4C14／G4C14基因型患者的2．22倍（95％讲，1．14～4、30，P=0．019）。2个多态位点合并分析结果显示，同时携带p53和p73野生基因型的患者，化疗有效率为7．7％；而携带1个、2个和≥3个p53和p73变异等位基因的患者，化疗有效率分别为34．8％、42．2％和40、7％。结论p53和p73基因遗传多态与晚期NSCLC患者对以铂类药物为主的化疗敏感性有关。

Objective It has been proposed that genetic polymorphisms in apoptosis-related genes might be associated with sensitivity of cancer cells to platinum-based chemotherapy. This study examined the relationship between p53 and p73 genetic polymorphisms and the response to platinum-based chemotherapy in patients with advanced non-small cell lung cancer （NSCLC）. Methods A total of 165 patients with advanced NSCLC treated with platinum-based chemotherapy were genotyped for the p53 codon 72 Pro→Arg and p73 exon 2 G4C14→A4T14 polymorphisms using PCR-RFLP and ARMS-PCR assays. Clinical response to the chemotherapy was obtained after 2 to 3 cycles. The adjusted odds ratios （ORs） and 95% confidence intervals （CIs） were calculated using unconditional logistic regression model. All statistical tests were twosided. Results The p53 Pro allele carriers had higher response rate than non-carriers （ OR = 2. 46; 95% CI= 1.11-5.45 ）. A higher response rate was also observed for the p73 G4C14/A4T14 or A4T14/ A4T14 genotype, compared with the G4C14/G4C14 genotype （ OR = 2. 22; 95% CI = 1.14-4.30）. When these two polymorphisms we/e combined to be analyzed, it was found that the response rate in those carrying the wild-type genotypes at both genes was only 7.7%, whereas the response rates in patients carrying 1, 2, or more than 2 variant alleles of p53 and p73 were 34. 8%, 42. 2% and 40.7%, respectively. Conclusion Those results suggest that p53 and p73 polymorphisms may be associated with clinical responsiveness to platinum-based chemotherapy in advanced NSCLC.