Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran

Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however , this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs), The causes of this high cancer burden in Iran remain obscure and do not appear to be related t o tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer r isk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5- 8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumor s (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surpris ingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation tha t is significantly less common (16% of mutations) in the compilation of ESC C mutations from other countries (chi (2) statistic, P < 0.0002), whereas t ransversions, which the literature shows to be common in ESCCs from non-Ira nian patients, were infrequent in the tumors we examined here. Elevated lev els of cyclooxygenase-2 and inducible nitric oxide synthase were observed i n 74 and 91%, respectively, of tumors from Tehran as determined by immunohi stochemistry, and high COX-2 expression correlated significantly with the p resence of a p53 mutation in the tumor, Mediators of the inflammatory respo nse in esophageal mucosa, perhaps in conjunction with specific dietary or c ultural practices in Iran, may contribute importantly to the p53 mutation l oad in Iranian ESCC patients.