Fusões do gene RET em painel multigênico para câncer de tireoide numa população infantojuvenil

Abstract

Introduction: Although it is a rare malignancy in the pediatric population, thyroid cancer, at this stage of life, is associated with advanced stages of the disease when compared to adulthood. The papillary type represents 80 to 90% of all thyroid carcinomas derived from follicular cells and presents a high rate of mutations and gene fusions, capable of influencing the clinical and biological behavior of the tumor. RET fusions are identified as important markers of tumor aggressiveness in the pediatric population, however, due to some factors, their frequency is highly variable. Objective: To retrospectively determine the frequency of RET gene fusions in paraffin-embedded samples of differentiated thyroid carcinoma from children, adolescents and young adults (<21 years) treated at the participating centers in the study. Material and methods: Retrospective, cross-sectional study with 79 cases of differentiated thyroid carcinoma, treated in four reference centers in the northeast region of Brazil, between January 2010 and March 2021. DNA was extracted from paraffin-embedded samples and directed to analysis through next-generation sequencing, where it was submitted to the HotSpot panel to determine point mutations, and to the Fusion panel to identify gene fusions. Results: Initially, five samples previously positive for the BRAFV600E mutation were detected and, as it is a genetic alteration that excludes RET/PTC rearrangements, they were not followed up with the evaluation of positivity for gene fusions. The HotSpot result showed 21/79 (26.6%) inconclusive results, 21/79 (26.6%) mutated and 37/79 (46.8%) wild type. Among the mutated, 10/21 (47.6%) cases were positive for BRAF mutation, 08/21 (38.1%) for EGFR, 04/21 (19.0%) for KRAS, 03/21 (14 .3%) for NRAS and 01/21 (4.8%) for PIK3CA, with occurrence of simultaneous point mutations. As for molecular analysis to detect gene fusions, 39/74 (52.7%) had inconclusive results, 10/74 (13.5%) were positive for a rearrangement and 25/74 (33.8%) were classified as wild type. Among the positive cases for gene fusions, 03 were of the RET gene (01 CCDC6::RET or RET/PTC1, 01 NCOA4::RET or RET/PTC3, and 01 TRIM24::RET or RET/PTC6); 04 were from the NTRK gene (03 ETV6::NTRK3 and 01 TPR::NTRK1); 02 PAX8::PPARG merges; and 01 STRN::ALK. Conclusion: In our study, the frequency of RET fusions was 8.6% (03/35), and younger individuals (<18 years) had a higher frequency of gene rearrangements, but the high rate of inconclusive results does not allow establishing the association of individuals with clinicalpathological aspects. Furthermore, BRAF gene mutations were the most frequent in the HotSpot panel, followed by EGFR, KRAS, NRAS and PIK3CA.