title: Iodine-131 dose dependent gene expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident.
abstract: The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4×44 K). Associations of differential gene expression (log(2)(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.
authors: Bundeswehr Institute of Radiobiology, Munich, Germany. michaelabend@bundeswehr.org
authors: Michael
authors: M
authors: Abend
authors: Ruth M
authors: RM
authors: Pfeiffer
authors: Christian
authors: C
authors: Ruf
authors: Maureen
authors: M
authors: Hatch
authors: Tetiana I
authors: TI
authors: Bogdanova
authors: Mykola D
authors: MD
authors: Tronko
authors: Armin
authors: A
authors: Riecke
authors: Julia
authors: J
authors: Hartmann
authors: Viktor
authors: V
authors: Meineke
authors: Houda
authors: H
authors: Boukheris
authors: Alice J
authors: AJ
authors: Sigurdson
authors: Kiyohiko
authors: K
authors: Mabuchi
authors: Alina V
authors: AV
authors: Brenner
mesh_terms: D000328:Adult; D047852:Chernobyl Nuclear Accident; D015331:Cohort Studies; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D007457:Iodine Radioisotopes; D012334:RNA, Neoplasm