Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

Ortiz-Cuaran Sandra, Hainaut Pierre

doi:10.3123/jemsge.33.141

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers, with 80% of the cases occurring in low resource countries. Its etiology is dominated by complex interplay between chronic infection by hepatitis virus B or C (HBV, HCV), metabolic diseases and exposure to environmental carcinogens. In areas of high incidence of HCC, the most common risk factors are chronic HB carriage and exposure to a mycotoxin, aflatoxin B1 (AFB1), which contaminates many staples and causes mutations at the third base of codon 249 in the TP53 tumor suppressor gene in hepatocytes (R249S mutation). In this review, we summarize studies using a very sensitive and quantitative detection method, short-oligonucleotide mass analysis, to measure R249S in cell-free DNA isolated from the plasma of asymptomatic subjects and patients with chronic liver disease and/or HCC. These studies have identified that high levels of R249S were strongly associated with HBV-related HCC. Low to intermediate levels of R249S, in contrast, were detectable in asymptomatic subjects exposed to AFB1, with seasonal variations informative of the complex interactions between mutagenesis by AFB1 and chronic infection by HBV. Overall, we suggest that formation of R249S occurs in response to AFB1 exposure, well ahead of cancer development, thus generating large populations of cells at high risk for neoplastic transformation. In addition, R249S mutations may inactivate pro-apoptotic activities of p53 and contribute to rendering hepatocytes resistant to liver cell destruction by chronic inflammation, thus limiting chronic liver disease symptoms.<br>

Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

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