249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients

<p>Abstract</p> <p>Background</p> <p>Ser-249 TP53 mutation (249^Ser) is a molecular evidence for aflatoxin-related carcinogenesis in Hepatocellular Carcinoma (HCC) and it is frequent in some African and Asian regions, but it is unusual in Western countries. HBV has been claimed to add a synergic effect on genesis of this particular mutation with aflatoxin. The aim of this study was to investigate the frequency of 249^Sermutation in HCC from patients in Brazil.</p> <p>Methods</p> <p>We studied 74 HCC formalin fixed paraffin blocks samples of patients whom underwent surgical resection in Brazil. 249^Sermutation was analyzed by RFLP and DNA sequencing. HBV DNA presence was determined by Real-Time PCR.</p> <p>Results</p> <p>249^Sermutation was found in 21/74 (28%) samples while HBV DNA was detected in 13/74 (16%). 249^Sermutation was detected in 21/74 samples by RFLP assay, of which 14 were confirmed by 249^Sermutant-specific PCR, and 12 by nucleic acid sequencing. All HCC cases with p53-249ser mutation displayed also wild-type p53 sequences. Poorly differentiated HCC was more likely to have 249^Sermutation (OR = 2.415, 95% CI = 1.001 – 5.824, p = 0.05). The mean size of 249^SerHCC tumor was 9.4 cm versus 5.5 cm on wild type HCC (p = 0.012). HBV DNA detection was not related to 249^Sermutation.</p> <p>Conclusion</p> <p>Our results indicate that 249^Sermutation is a HCC important factor of carcinogenesis in Brazil and it is associated to large and poorly differentiated tumors.</p

Benzo[a]pyrene, Aflatoxine B1 and Acetaldehyde Mutational Patterns in TP53 Gene Using a Functional Assay: Relevance to Human Cancer Aetiology

Mutations in the TP53 gene are the most common alterations in human tumours. TP53 mutational patterns have sometimes been linked to carcinogen exposure. In hepatocellular carcinoma, a specific G>T transversion on codon 249 is classically described as a fingerprint of aflatoxin B1 exposure. Likewise G>T transversions in codons 157 and 158 have been related to tobacco exposure in human lung cancers. However, controversies remain about the interpretation of TP53 mutational pattern in tumours as the fingerprint of genotoxin exposure. By using a functional assay, the Functional Analysis of Separated Alleles in Yeast (FASAY), the present study depicts the mutational pattern of TP53 in normal human fibroblasts after in vitro exposure to well-known carcinogens: benzo[a]pyrene, aflatoxin B1 and acetaldehyde. These in vitro patterns of mutations were then compared to those found in human tumours by using the IARC database of TP53 mutations. The results show that the TP53 mutational patterns found in human tumours can be only partly ascribed to genotoxin exposure. A complex interplay between the functional impact of the mutations on p53 phenotype and the cancer natural history may affect these patterns. However, our results strongly support that genotoxins exposure plays a major role in the aetiology of the considered cancers