title: Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications.
abstract: Molecular genetic aberrations and the related phenotypes were investigated in 191 papillary thyroid carcinomas (PTCs) from patients exposed at young age to radioiodine released from the Chernobyl reactor. A high prevalence of RET gene rearrangements (62.3%) with a significant predominance of ELE1/RET (PTC3) over H4/RET (PTC1) rearrangements was found in PTCs of the first post-Chernobyl decade. NTRK1 rearrangements were rare (3.3%). In 3.3%, we observed novel types of RET rearrangements: GOLGA5/ RET (PTC5), HTIF/RET (PTC6), RFG7/RET (PTC7), and an as yet undefined RFGX/RET.RET rearrangements, preferentially ELE1/RET, are related to rapid tumor development. At longer intervals after exposure to ionizing radiation, the prevalence of RET rearrangements declines with a shift from ELE1/RET to H4/RET, most significantly in female patients. The prevalence of specific types of rearrangements is independent of age at irradiation. A significantly higher prevalence of ELE1/RET was observed in the most heavily contaminated Oblasts, Gomel and Brest, suggesting a preferential formation of this type of rearrangement after high thyroid doses. RET rearrangement is related to aggressive growth: Rearrangement-positive PTCs were in a more advanced pT category and more frequently in the pN1 category at presentation than rearrangement-negative PTCs. ELE1/RET is related to the solid variant of PTC, H4/RET more frequently to typical papillary structures. The genotype/phenotype evaluation of post-Chernobyl PTCs reveals a characteristic spectrum of gene rearrangements that lead to typical phenotypes with important biological and clinical implications.
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany. hm.rabes@lrz.uni-muenchen.de
authors.forename: H M
authors.initials: HM
authors.lastname: Rabes
authors.forename: E P
authors.initials: EP
authors.lastname: Demidchik
authors.forename: J D
authors.initials: JD
authors.lastname: Sidorow
authors.forename: E
authors.initials: E
authors.lastname: Lengfelder
authors.forename: C
authors.initials: C
authors.lastname: Beimfohr
authors.forename: D
authors.initials: D
authors.lastname: Hoelzel
authors.forename: S
authors.initials: S
authors.lastname: Klugbauer
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004307:Dose-Response Relationship, Radiation; D029721:Drosophila Proteins; D005260:Female; D015321:Gene Rearrangement / Q000528:radiation effects; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009367:Neoplasm Staging; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D018788:Radioactive Hazard Release; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020917:Receptor, trkA / Q000235:genetics*; D012737:Sex Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D013997:Time Factors
chemical_list: D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; C416649:Ret protein, Drosophila