비소세포폐암에서 p53 종양억제 유전자와 K-ras 유전자의 돌연변이가 임상상에 미치는 영향

Abstract

Objective: A multistep process of gene alterations is required for tumor formation, p53 gene mutation is the most frequent and K-ras gene mutation places second in the gene abnormalities of non-small cell lung cancer (NSCLC). The effect by the mutations of the p53 and ras genes on clinical manifestation is still highly controversial Little is known about the interaction between them in NSCLC. The present study was designed to investigate the effect by the mutations of the p53 tumor suppressor gene and K-ras oncogene on clinical manifestation, and the interaction between the mutations of two genes in the Korean NSCIC. Methods: Fifty-eight patients were enrolled in this study who had been diagnosed as having NSCLC from stage I to stage Ⅲ. They all had been alive for more than one month without any complication after curative resection. The paraffin-embedded lung tissues after resection were used to investigate the p53 expression by immunohistochemical staining, the mutations of the p53 and K-ras genes by polymerase chain reactionsingle strand conformation polymorphism(PCR-SSCP) and nucleotide sequencing. Results: p53 protein was overexpressed in 25.9% by immunohistochemical staining. Overexpression was significantly more frequent in epidermoid carcinoma(p=0.01634). But there was no significant difference between the overexpression group and the negative expression group according to stage and survival. By PCR-SSCP analysis, the mobility shift of the p53 gene was found in 29.1%. There was no significant difference between the groups with and without mobility shift according to cell type, stage and survival. By nucleotide sequencing, p53 gene mutation was 37.9%. The locations of mutation were dispersed among numerous codons and the modes of mutation were also diverse. There was also no significant difference between the groups with and without mutation according to cell type, stage and survival. K-ras gene mutation was 24.1% and only in codon 12 by nucleotide sequencing. Although there was no significant difference between the groups with and without mutation according to cell type or stage, K-ras gene mutation carried a significantly worse prognosis in NSCLC (overall survival p=0.0391, disease-free survival p=0.0318). When the patients were divided into 4 groups according to p53 gene mutation and K-ras gene mutation. there was also no significant difference among any group according to cell type or stage. The prognosis became worse if K-ras gene mutation accompanied(overall survival p=0.0021, disease-free survival p=0.0166). Only the stage(p=0.0313) and K-ras gene mutation(p=0.0457) were significant prognostic factors by Cox regression test. An analysis in stage III showed the significantly shorter survival period in the patients with K-ras gene mutation. K-ras gene mutation, therefore, was confirmed as the independently significant prognostic factor separately from stage. Conclusion: p53 gene mutation had no clinical or prognostic significance because of scattered locations and diverse modes of mutation in contrast to K-ras gene mutation, which had a significantly negative effect on the prognosis of NSCLC. p53 and K-ras gene mutations were apparently independent genetic alterations which played different roles in the clinical manifestation and prognosis of NSCLC.