Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced nonsmall cell lung cancer

作者：Han Ji Youn^*; Lee Geon Kook; Jang Dae Ho; Lee Sung Young; Lee Jin Soo

来源：Cancer, 2008, 113(4): 799-807.

DOI：10.1002/cncr.23668

• nonsmall cell lung cancer
• NSCLC
• MDM2
• p53 expression

BACKGROUND. The purpose of the study was to investigate whether polymorphisms of p53 codon 72 (Arg72Pro) and MDM2 SNP309 (309T > G) affect p53 expression and the clinical outcome of patients with advanced nonsmall cell lung cancer (NSCLC).
METHODS. A total of 148 NSCLC patients, previously enrolled in 2 different prospective clinical trials, were genotyped for p53 Arg72Pro and MDM2 309T > G polymorphisms. Immunohistochemical staining of p53 protein was performed on 61 tumor samples. Genotypes were correlated with p53 expression, clinicopathologic factors, tumor response, and survival. Multivariate logistic or Cox regression analyses were used to adjnst for possible confounding variables.
RESULTS. The distribution of sex, age, performance status, stage, tumor histology. and smoking habit was not significantly different among polymorphism variants. However, a significant association was observed between p(53) Arg72Pro polymorphism and primary resistance to chemotherapy. Patients with the Pro/Pro variant were more likely to be resistant to first-line chemotherapy, especially the irinotecan phis cisplatin regimen, than those with Arg/Arg or Arg/Pro variants (60%) vs 27%, P = .014). In multivariate analysis, the ProPrro genotype was strongly predictive for shorter progression-free survival (PFS) (hazard ratio vertical bar HR vertical bar = 1.952, P = .01). The p53 overexpression was associated with MDM2 SNP309. The TT genotype showed more p53 overexpression than TG or GG genotypes (P = .036). In mulltivariate analysis, the MDM(2) TT genotype was independently predictive for longer survival (HR = 1.742, P =.032).
CONCLUSIONS. The p53 72Pro/Pro variant was predictive for primary resistance to chemotherapy and shorter progression-free snrvival. The MDM2 SNP309 was associated with less p53 overexpression and prognostic for worse survival. Genetyping these polyrnorphisms may be Useful for predicting the clinical outcome of advanced NSCLC.

• 出版日期2008-8-15