Rearranjos dos genes NTRK no carcinoma diferenciado de tireoide em crianças, adolescentes e adultos jovens: estudo multicêntrico em centros de referência da Bahia e da Paraíba.

Abstract

Introduction: Differentiated thyroid carcinoma (DTC) is rare in children, ranging from 0.3-0.5% of all pediatric neoplasms. However, it remains the most common endocrine malignancy in this age group and represents the third most common pediatric solid tumor. The prevalence and type of mutations in genes involved in the DTC oncogenesis differ between adults and children, although pediatric data are still limited. The role of these changes in the initiation and progression of this carcinoma and the prevalence and potential associations of distinct molecular markers with clinical and pathological characteristics of tumor aggressiveness and/or poor clinical outcome are not fully consolidated. Recently, NTRK fusions have been identified as important markers of tumor aggressiveness in pediatric DTC, however, its prevalence is highly variable. Objectives: To track the presence of NTRK fusions in tumor samples from children, adolescents and young adults (under 21 years old); the samples were fixed in formalin and kept in paraffin blocks from children, adolescents and young adults (under 21 years old), using immunohistochemistry (IH), and to investigate and confirm the prevalence of NTRK gene rearrangements through next-generation sequencing (NGS) in the population. Secondarily, to investigate the clinical and pathological and molecular aspects (positivity for BRAF, NRAS, KRAS, EGFR, PIK3CA mutations). Material and Methods: Retrospective multicenter and cross-sectional study involving tumor samples from 79 non-consecutive DTC cases in pediatric patients, adolescents or young adults (under 21 years old) that were treated at 04 referral centers for cancer treatment in Bahia and Paraiba, between January, 2010 and March, 2021. All samples were submitted to IH for NTRK fusion tracking and to hotspot panel for gene mutations detection. IH positive cases were submitted to NGS in order to confirm the positive result. NGS were also performed in all IH negative cases to investigate the fusion, except for those tumors with the BRAFV600E mutation (74 samples). Positive and negative results were considered valid tests. Clinical and anatomopathological reports were obtained from slides review and electronic system. Descriptive Analysis: Quantitative variables were evaluated with the Mann-Whitney test. Regarding qualitative variables the chi-square test or the Exact Fisher's test was applied. Values of p<0.05 were considered statistically significant. Results: Positivity pan-TRK prevalence for NTRK fusion tracking in 79 tumors samples from pediatric and young adults with DTC was 3,7% (03 cases). The NTRK fusion prevalence confirmed using NGS technique for 35/74 valid tests in our casuistry was 11,4%: 03 ETV6-NTRK3 and 01 TPR-NTRK1 rearrangements. In 03 positive samples in IH, the frequency of NTRK fusions was 0%. The study was unable to establish NTRK fusion positivity association with other clinical and pathological and molecular aspects of tumoral aggressiveness. Conclusion: The absence of NTRK fusion confirmation by NGS technique in IH positive samples suggests a low sensitivity of the IH method for tracking NTRK rearrangements, and the low prevalence of NTRK fusions in this study suggests a low NTRK fusion frequency in the evaluated population.