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Molecular Signatures of Environmental Mutagens in Hepatocellular Carcinoma

机译：肝细胞癌中环境突变基因的分子特征

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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 theTP53 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 identied that high levels of R249S were strongly associated with HBV-related HCC. Low to intermediate levels ofR249S, 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.
机译：肝细胞癌（HCC）是第五大最常见的癌症之一，其中80％的病例发生在资源贫乏的国家。其病因主要由乙型或丙型肝炎病毒（HBV，HCV）的慢性感染，代谢性疾病和环境致癌物之间的复杂相互作用所决定。在HCC高发地区，最常见的危险因素是慢性HB携带和暴露于霉菌毒素黄曲霉毒素B1（AFB1），它会污染许多主食并导致肝细胞TP53抑癌基因的249位密码子第三碱基发生突变。 （R249S突变）。在这篇综述中，我们总结了使用非常敏感和定量的检测方法，即短寡核苷酸质量分析，来测量从无症状受试者和慢性肝病和/或HCC患者血浆中分离的无细胞DNA中的R249S。这些研究已经确认，高水平的R249S与HBV相关的HCC密切相关。相比之下，在暴露于AFB1的无症状受试者中可检测到低至中等水平的R249S，季节性变化说明AFB1诱变与HBV慢性感染之间存在复杂的相互作用。总体而言，我们建议R249S的形成是在AFB1暴露后发生的，远远早于癌症的发展，从而产生大量细胞，处于发生肿瘤转化的高风险中。此外，R249S突变可能使p53的促凋亡活性失活，并导致肝细胞具有抵抗慢性炎症引起的肝细胞破坏的能力，从而限制了慢性肝病的症状。

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