Tanase Anna-Maria, Marchio Agnès, Dumitrascu Traian, Dima Simona, Herlea Vlad, Oprisan Gabriela, Dejean Anne, Popescu Irinel, Pineau Pascal
Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, rue du Docteur Roux, Paris, France.
J Expo Sci Environ Epidemiol. 2015 May;25(3):256-63. doi: 10.1038/jes.2014.16. Epub 2014 Apr 16.
Genomic analysis of hepatocellular carcinoma (HCC) has been shown to provide clues about local risk factors. In the last decades, the mortality from malignant liver tumors increased sharply in Romania, where both hepatitis viruses and environmental pollutants are known to be highly prevalent. To date, HCC from this country has not been subject to molecular characterization. We analyzed a series of 48 consecutive HCC cases. Point mutations were searched in 9 nuclear genes and the mitochondrial D-loop. Oxidative stress response was monitored through measurement of gene expression (NRF2, KEAP1, SRXN1, and CES1) by qRT-PCR. An atypical mutation spectrum was observed, as more than 40% of DNA changes were oxidative stress-associated T>C or T>G lesions (T>S). These mutations affected primarily genes encoding for β-catenin and NRF2 (P<0.0001). Besides, tumors from patients born in Greater Bucharest carried TP53 mutations more frequently than others (45 vs 10%, P=0.02). Finally, a R249S mutation of TP53, well-known hallmark of aflatoxin B1 exposure, was found. Our findings indicate, therefore, that distinct mutagenic processes affect Romanian patients with HCC. Further analyses are now warranted in order to identify causal lifestyle or environmental factors.
肝细胞癌（HCC）的基因组分析已被证明能提供有关局部危险因素的线索。在过去几十年里，罗马尼亚恶性肝肿瘤的死亡率急剧上升，已知该国肝炎病毒和环境污染物都高度流行。迄今为止，该国的HCC尚未进行分子特征分析。我们分析了连续的48例HCC病例。在9个核基因和线粒体D环中搜索点突变。通过qRT-PCR测量基因表达（NRF2、KEAP1、SRXN1和CES1）来监测氧化应激反应。观察到一种非典型的突变谱，因为超过40%的DNA变化是与氧化应激相关的T>C或T>G损伤（T>S）。这些突变主要影响编码β-连环蛋白和NRF2的基因（P<0.0001）。此外，出生在大布加勒斯特的患者的肿瘤比其他患者更频繁地携带TP53突变（45%对10%，P=0.02）。最后，发现了TP53的R249S突变，这是黄曲霉毒素B1暴露的著名标志。因此，我们的研究结果表明，不同的诱变过程影响罗马尼亚的HCC患者。现在有必要进行进一步分析，以确定因果生活方式或环境因素。
