Abstract 1495: Analysis of p53 mutations in human esophageal cancer

Abstract

Abstract Studies on p53 mutations occurring in human tumors have the potential to provide information on causes of human cancer. This is relevant for cancer risk assessment on new products. A database of p53 mutations in human tumors is maintained by Olivier and Hainaut at IARC. We analyzed esophageal squamous cell carcinoma (ESCC), a cancer with known geographic hot spots and life style associations. IARC search allows the rapid determination of sequence distribution, codon location, and strand bias of p53 mutations in tumors stratified by pathology, gender, and lifestyle factors such as tobacco and alcohol use. Although proportions of DNA sequence changes in tumors are provided in IARC profiles, the nature of sequence changes at each base pair is not. Of particular interest are the sequence changes at hot spots. We analyzed the DNA sequence changes among 1032 esophageal mutations occurring at hot spot codons 175, 248, 273, and 282. These are all CpG sites encoding arginine. However, the distribution of mutations was strikingly different at the different sites. At codon 175 (CGC) 98% of the mutations were CAC, virtually all showing strand bias, i.e. G to A from the G containing strand. At codon 248 (CGG), the mutation distribution was 49%TGG and 40% CAG, showing no strand bias, i.e. equally G to A or C to T. At codon 273 (CGT), the mutation distribution was 49% CAT, 33% TGT, and 12% CTT, demonstrating some strand bias but a broader distribution of sequence changes. At codon 282 (CGG), 92% were TGG, again showing striking strand bias. Codons 248 and 282 had identical target sequences but different distributions in the tumors, 282 showing strand bias and 248 showing equivalent distribution of mutations on both strands of DNA. A biased distribution of DNA sequence changes could be related to causal DNA lesions, asymmetric DNA repair, and/or selection of particular mutant phenotypes during tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1495.