title: A dose-dependent decrease in the fraction of cases harboring M6P/IGF2R mutations in hepatocellular carcinomas from the atomic bomb survivors.
abstract: The risk for hepatocellular carcinoma (HCC) development is significantly heightened in the atomic bomb survivors, but the mechanism is unclear. We have previously reported finding a radiation dose-dependent increase in HCCs with TP53 mutations from the survivors. We now show that, in the same HCC samples, the frequency of 3'-untranslated region (3'UTR) mutations in M6P/IGF2R, a candidate HCC tumor suppressor gene, decreases with dose (P = 0.0091), implying a radiation dose-dependent negative selection of cells harboring such mutations. The fact that they were in the 3'UTR implicates changes in transcript stability rather than in protein function as the mechanism. Moreover, these M6P/IGF2R 3'UTR mutations and the TP53 mutations detected previously were mutually exclusive in most of the tumors, suggesting two independent pathways to HCC development, with the TP53 pathway being more favored with increasing radiation dose than the M6P/IGF2R pathway. These results suggest that tumors attributable to radiation may be genotypically different from tumors of other etiologies and hence may provide a way of distinguishing radiation-induced cancers from "background" cancers--a shift from the current paradigm.
authors.affiliation: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan. kiwamoto@mednet.ucla.edu
authors.forename: Keisuke S
authors.initials: KS
authors.lastname: Iwamoto
authors.forename: Shiho
authors.initials: S
authors.lastname: Yano
authors.forename: Chad L
authors.initials: CL
authors.lastname: Barber
authors.forename: Donald G
authors.initials: DG
authors.lastname: MacPhee
authors.forename: Shoji
authors.initials: S
authors.lastname: Tokuoka
mesh_terms: D001822:Body Burden; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004307:Dose-Response Relationship, Radiation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008360:Mannosephosphates / Q000235:genetics; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology* / Q000235:genetics*; D009689:Nuclear Warfare / Q000706:statistics & numerical data*; D011829:Radiation Dosage; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D017741:Survivors / Q000706:statistics & numerical data
chemical_list: D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate