title: Mutation spectrum of hepatocellular carcinoma from eastern-European patients betrays the impact of a complex exposome.
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.
authors.affiliation: Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Tanase
authors.affiliation: Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, rue du Docteur Roux, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Marchio
authors.affiliation: Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
authors.forename: Traian
authors.initials: T
authors.lastname: Dumitrascu
authors.affiliation: Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
authors.forename: Simona
authors.initials: S
authors.lastname: Dima
authors.affiliation: Department of Pathology, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
authors.forename: Vlad
authors.initials: V
authors.lastname: Herlea
authors.affiliation: Molecular Biology Laboratory, National Institute for Research/Development of Microbiology and Immunology Cantacuzino, Splaiul Independentei, Bucharest, Romania.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Oprisan
authors.affiliation: Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, rue du Docteur Roux, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
authors.affiliation: Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, Bucharest, Romania.
authors.forename: Irinel
authors.initials: I
authors.lastname: Popescu
authors.affiliation: Unité d'Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, rue du Docteur Roux, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pineau
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000187:drug effects; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017354:Point Mutation / Q000187:drug effects*; D011446:Prospective Studies; D012307:Risk Factors; D012383:Romania
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D004785:Environmental Pollutants; D005819:Genetic Markers
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