An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico

Abstract

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.

Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma

“…We first analyzed the mutational status of TP53 in these cell lines and identified in IST-MES 2 a p.Arg249Ser p53 mutation, which had never been described in mesothelioma. This mutation, lying in the DNAbinding domain, is considered an aflatoxin-associated mutational hotspot; 38 however, it remains to be established whether it could have a causal role in mesothelioma development. Then, we showed that both RITA and nutlin-3 are indeed able to increase p53 levels in mesothelioma cell lines.…”

The adaptive imbalance in base excision–repair enzymes generates microsatellite instability in chronic inflammation

“…DNA isolation for MSI has been described previously (18). A PCR-based approach (19) of microsatellite polymorphism analysis was used.…”

A case-control study of risk factors for hepatocellular carcinoma in Henan, China.

“…There is much data indicating that peanuts and corn are commonly contaminated with aflatoxin in China and other parts of the world. [15][16][17][18] In geographic areas with a high incidence of HCC, exposure to dietary aflatoxin B1 and chronic HBV infection are synergistic risk factors. 19,20 In this study, we found that there was a significant association between consumption of peanuts or corn and HCC.…”