Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers, with 80z 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, a‰atoxin 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 identiˆed 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 in‰ammation, thus limiting chronic liver disease symptoms.

Risk assessment of aflatoxins in food

“…In HCC cell lines, the R249S variant was found to lack the capacity to bind to p53 response elements and to transactivate p53 target genes (Gouas et al, 2010). Studies indicate a strong association between high levels of R249S and HBV-related HCC, whereas low to intermediate levels of R249S were detectable in asymptomatic subjects exposed to AFB1 (Ortiz-Cuaran and Hainaut, 2011).…”

Aflatoxins Contamination in Feed Commodities: From Occurrence and Toxicity to Recent Advances in Analytical Methods and Detoxification

“…In hepatocellular carcinoma (HCC) cell lines, the R249S variant demonstrated a capacity to attach to p53 response elements and trigger the activation of p53 target genes [34]. The presence of high R249S levels is intricately linked to HBV-related HCC, while lower to medium levels appear in asymptomatic individuals exposed to AFB1 [35]. Recent research has delved into the broader mutational patterns caused by AFB1 exposure [36,37].…”