In Vitro Recapitulating of TP53 Mutagenesis in Hepatocellular Carcinoma Associated With Dietary Aflatoxin B1 Exposure

Besaratinia, Ahmad; Kim, Sang-in; Hainaut, Pierre; Pfeifer, Gerd P.

doi:10.1053/j.gastro.2009.06.002

Cited by 77 publications

(72 citation statements)

References 52 publications

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“…Accumulation of mutations without concomitant reduction in embryonic progeny survival indicates that sequencing provides a more sensitive genotoxicity assay than measuring reduced survival of progeny. The aflatoxin signature matches mutation profiles reported in the TP53 gene in human aflatoxin-induced hepatocellular carcinomas, namely, a preponderance of C>T transitions and C>A transversions (equivalently, G>A and G>T) occurring with a strand bias indicative of evidence of transcription-coupled nucleotide excision repair (Petitjean et al 2007;Besaratinia et al 2009). …”

Section: Resultssupporting

confidence: 66%

C. eleganswhole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency

et al. 2014

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Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage–fusion–bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling “chromoanasynthesis,” a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.

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Section: Resultssupporting

confidence: 66%

C. eleganswhole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency

et al. 2014

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“…Recent evidence confirmed that this position is a preferential site for AFB1 adduct formation. 37 In Thailand, the main dietary sources of AFB1 are maize and groundnuts. Individual exposure to AFB1 has been estimated to range from 53 and 73 ng/kg/day, although this figure is likely to vary widely among different geographic areas and ecological zones.…”

Section: Role Of Aflatoxin Afb1mentioning

confidence: 99%

Risk Factors for the Development of Hepatocellular Carcinoma in Thailand

Chitapanarux¹,

Phornphutkul²

2015

JCTH

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions.

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“…AFB1 is metabolized in the liver into an epoxide that covalently binds to the N7 position of guanine at the third base of codon 249 in the TP53 gene (AGG, encoding arginine), resulting in a transversion mutation which is extremely rare in cancers other than liver (AGT, encoding serine, R249S mutation, mutant protein p.R249S) (27,28). There is a strong ecological concordance between high exposure to AFB1 and a high proportion of R249S-positive HCC (up to 70z in parts of China and Africa).…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

Ortiz-Cuarán

Hainaut

2011

Genes and Environment

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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.

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In Vitro Recapitulating of TP53 Mutagenesis in Hepatocellular Carcinoma Associated With Dietary Aflatoxin B1 Exposure

Cited by 77 publications

References 52 publications

C. eleganswhole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency

C. eleganswhole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency

Risk Factors for the Development of Hepatocellular Carcinoma in Thailand

Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

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