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.