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  • Original Article
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Mutation spectrum of hepatocellular carcinoma from eastern-European patients betrays the impact of a complex exposome

Journal of Exposure Science & Environmental Epidemiology volume 25, pages 256–263 (2015)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to the Plate-forme Génomique no. 1 of the Institut Pasteur (Sylviane Bouchier and Catherine Gouyette). We thank Kathleen Victoir and Marc Jouan for their support. We feel greatly indebted to Camille Baron for her help in setting up the protocol document and the case report form. We thank Jacob Seeler for critical reading of the manuscript. This work, part of the ACIP2006 (Action Concertée Interpasteurienne), was funded by the Division International of the Institut Pasteur and by the French National League against Cancer (LNCC).

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  1. Anna-Maria Tanase and Agnès Marchio: These authors should be considered as co-first authors

Authors and Affiliations

  1. Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania

    Anna-Maria Tanase, Traian Dumitrascu, Simona Dima & Irinel Popescu

  2. Unité d’Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, rue du Docteur Roux, Paris, France

    Agnès Marchio, Anne Dejean & Pascal Pineau

  3. Department of Pathology, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania

    Vlad Herlea

  4. Molecular Biology Laboratory, National Institute for Research/Development of Microbiology and Immunology Cantacuzino, Splaiul Independentei, Bucharest, Romania

    Gabriela Oprisan

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Tanase, AM., Marchio, A., Dumitrascu, T. et al. Mutation spectrum of hepatocellular carcinoma from eastern-European patients betrays the impact of a complex exposome. J Expo Sci Environ Epidemiol 25, 256–263 (2015). https://doi.org/10.1038/jes.2014.16

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