TP53 MUTATIONAL PATTERN IN SPANISH AND POLISH NONSMALL CELL LUNG-CANCER PATIENTS - NULL MUTATIONS ARE ASSOCIATED WITH POOR-PROGNOSIS

Inactivation of TP53 tumor suppressor gene is the most frequent molecu lar alteration in NSCLC, involving up to 60% of cases, Furthermore, TP 53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet differences, Nearly 95% of TP53 perturbatio ns affect codons included within exons 5-8 which encode for almost the entire DNA-binding domain, In this study we addressed the possible pr ognostic value of the molecular alterations identified in exons 5-8 of the TP53 gene in DNAs from 151 paraffin-embedded NSCLC sections corre sponding to 59 Spanish and 92 Polish stage I-IIIA resected patients, P CR/single-strand conformation polymorphism (SSCP) analysis revealed th at the occurrence of TP53 exon 5-8 mutations was 17/59 (29%) in the Sp anish cohort and 17/92 (18%) in the Polish group, However, when DNA se quencing analysis was performed, these frequencies were reduced becaus e of the presence of SSCP-false positive, intronic and silent mutation s and polymorphisms, Fifteen of the 59 Spanish NSCLC tumors (25%) harb ored TP53 mutations affecting exons 5-8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53, Our results indicate that the occurrence of TP53 mutations affecting exon 5-8 coding sequences in some European N SCLC populations may be lower than previously reported, and that the T P53 mutational patterns of these cohorts differ somewhat, The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relative ly high percentage of null mutations (5/59, 8%) while the Polish patie nts mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%), Moreover, most TP53 missense mutatio ns in the Spanish group were located outside the conserved regions, wh ereas the same mutations in the Polish group affected conserved amino acids, Furthermore, the Polish patients harbored a high percentage of G-->A transitions (most of them at non-CpG sites), while G-->T transve rsions were predominant in the Spanish group, Our findings suggest tha t there may be different racial or exogenous factors in these two popu lations which may help to explain both the distinct TP53 mutational pa ttern and the lower frequency obtained in the Polish group, The presen ce of missense mutations did not confer a worse clinical outcome in th ese subsets of NSCLC patients, However, patients whose tumors containe d null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P =0.008), These findings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.