Jornal de Carcinogênese e Mutagênese

Abstrato

P53- The Molecular Guardian Crashes in Gastric Adenocarcinomas - A Study in an Ethnic Kashmiri Population

Safiya Abdullah, Syed Sameer A, Dil-Afroze, Nidda Syeed, Das BC and Mushtaq A. Siddiqi

Genetic instability underlies the etiology of multistep gastric carcinogenesis. The p53 mutations observed in tumors represent the expression of such instability by allowing the accumulation of genetic alterations caused by multiple mechanisms. The present study was conducted to investigate the nature and frequency of TP53 mutations in patients with gastric adenocarcinomas of Kashmir valley. Tumor samples from 30 patients with primary gastric adenocarcinomas undergoing radical gastrectomy were evaluated. The mutational status of the p53 (exons 5 to 8) was screened by PCR-SSCP analysis followed by direct sequencing. Of all 30 gastric adenocarcinomas including ten intestinal types and twenty diffuse types, 20% patients (6/30) harbored mutations in the p53 gene. Overall, twenty-one mutations were found in TP53 in 30 patients included in this study. Mutations were found at codon 142 (3 cases) of exon 5, codon 144 (1 case) in exon 5, codon 147 (1 case) in exon 5, codon 157 (1 case) in exon 5, codon 169 (2 cases) in exon 5, codon 170 (3 cases) in exon 5, codon 172 (1 case) in exon 5, codon 173 (3 cases) in exon 5, codon 179 (3 cases) in exon 5, codon 180 (1 case) in exon 5, codon 213 (1 case) in exon 6, the insertional mutation was between codon 216 & 217 (1 case) in exon 6 and codon 287 in exon 8 (1 case). The mutation pattern comprised of 12 insertions, 6 substitutions (all transversions) and 3 deletions. All the twelve insertions represented frame-shift mutations. The six single-base substitutions leading to aminoacid substitution included four missense mutations and a single silent mutation. The mutation effect data was found to be significant (p< 0.05). This study exhibited signifi cant amount of mutation in exon 5 (OR=90.25 and p<0.05 within the CI of 12.47-652.89) of TP53 in the gastric adenocarcinoma patients from Kashmir valley. Comparison of mutation profi le with other ethnic populations and regions refl ected both differences and similarities indicating co-exposure to a unique set of risk factors. The differences could be due to exposure to explicit environmental carcinogens, different lifestyle, dietary or cultural practices of Kashmiris being an ethnic population that need further investigations. The direct sequencing results, therefore, shall help in understanding the molecular events associated with progression and metastasis in gastric carcinoma. Conclusions: p53 gene mutation incites the pathogenesis of human gastric adenocarcinomas.