MUTATIONS IN EXON-7 AND EXON-8 OF P53 AS POOR PROGNOSTIC FACTORS IN PATIENTS WITH NONSMALL CELL LUNG-CANCER

This study was performed to clarify the different effects of each muta nt exon of p53 as indicators of a poor prognosis in patients with non- small cell lung cancer (NSCLC), Tumor tissues of 204 patients with NSC LC were analysed; 96 tumors were stage I, 22 stage II, and 86 stage II I. DNA was extracted from frozen specimens and polymerase chain reacti on-single strand conformation polymorphism (PCR-SSCP) and direct seque ncing were performed to investigate mutations of p53 from exon 5 to ex on 8, Seventy-five patients with NSCLC (36.8%) had mutations in p53 wh ich included 72 cases of missense mutations and three cases of non-mis sense mutations, The overall survival rate of patients with mutant p53 adenocarcinomas was strikingly worse than that of patients whose tumo rs had wild-type p53 (35.7% vs 53.8%; P = 0.041), but no significant d ifference in survival was found in the patients with NSCLC and squamou s cell carcinoma, Mutations in exon 5 of p53 occurred in 33 cases (16. 2%), mutation in exon 6 was detected in only one case (0.5%), mutation s in exon 7 in 20 cases (9.8%), and mutations in exon 8 in 18 cases (8 .8%), The overall survival rate of patients with mutations in exon 7 w as worse than that of patients with wild-type p53 in NSCLCs and adenoc arcinomas (42.9% vs 56.0%; P = 0.025 and 33.3% vs 53.8%; P = 0.048, re spectively), whereas the overall survival of patients with mutations i n exon 5 was almost the same as that of patients with wild-type p53, I n addition, the overall survival rate of patients with mutations in ex on 8 was strikingly worse than that of patients with wild-type p53 in NSCLCs, adenocarcinomas and squamous cell carcinomas (22.9% vs 56.0%; P < 0.001, 19.0% vs 53.8%; P = 0.004 and 33.3% vs 62.5%; P = 0.042, re spectively). Multivariate analysis with the Cox regression model of pa tients with NSCLC, adenocarcinoma and squamous cell carcinoma indicate d that mutations in exon 8 mere best correlated with the overall survi val rate, followed by lymph node status (P < 0.001, P = 0.015 and P = 0.006, respectively), and mutations in exon 7 of NSCLC were also revea led to have good correlation, followed by lymph node status and mutati ons in exon 8 (P = 0.031), Mutation of p53 was a poor prognostic facto r for adenocarcinoma as described previously, Moreover, mutations in e xon 8 were more useful indicators of prognosis not only for adenocarci noma but also for NSCLC, Worse overall survival of the patients with m utations in exon 8 of p53 was suggested to be associated with codon 27 3 mutations as well as mutations between codon 280 and 285 included in to the H2 alpha helix corresponding to residues 278-286, These results suggested that abnormal conformation of H2 alpha helix might play an important role not only in the loss of normal function but also in the acquisition of tumorigenesis, Investigation of mutations in exon 8, e specially codon 273 mutation and mutant H2 alpha helix was considered to be a clinically useful approach for determining the prognosis of pa tients with NSCLC.