title: Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers.
abstract: Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ricarte-Filho
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Maria E R
authors.initials: ME
authors.lastname: Garcia-Rendueles
authors.forename: Cristina
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: Francesca
authors.initials: F
authors.lastname: Voza
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Tetyana
authors.initials: T
authors.lastname: Bogdanova
authors.forename: Geraldine A
authors.initials: GA
authors.lastname: Thomas
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D047852:Chernobyl Nuclear Accident; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D050596:Oncogene Fusion; D047495:PPAR gamma / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics; D011989:Receptors, Thyrotropin / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D014455:Ukraine; D055815:Young Adult; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004273:DNA, Neoplasm; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D048493:Proto-Oncogene Proteins B-raf; D050783:Proto-Oncogene Proteins c-ets; D051096:Proto-Oncogene Proteins c-ret; D020812:Receptor, trkC; D011989:Receptors, Thyrotropin; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C492429:AGK protein, human; C099282:RET protein, human; C482119:BRAF protein, human