Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

Abstract

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma

“…** Analysis of the presence of other oncogenic drivers and gene fusions (e.g. RET/PTC and NTRK-fusions) may be considered in Bethesda 3, 4, or 5 due to the fact of increasing awareness that these are also associated with the presence of PTC ( 39 ). In case a BRAF V600E mutation is found, the risk of the thyroid nodule being malignant is high but needs to be confirmed, for example, by frozen section during thyroid surgery.…”

Age of Onset of Receptor Tyrosine Kinase Fusions Drives Distinct Biologic Outcomes in Thyroid Cancer

“…Pediatric PTCs are known to be more prone to develop nodal and distant metastases than PTCs in adults. 6 The study by Franco et al 2 investigates differences in metastatic tropism on the basis of their tumor drivers within a pediatric cohort, as compared with adults. Consistent with previous studies, 7 Franco found that pediatric PTCs driven by RET or NTRK fusions more frequently develop nodal metastases than fusion-negative tumors.…”

Paediatric differentiated thyroid carcinoma: a UK National Clinical Practice Consensus Guideline

“…While it is rare in CYP with DTC to require non-standard therapy, molecular genetic testing is likely to be increasingly used to direct targeted palliative therapies (see Recommendation 57). Future trials can also consider the inclusion of molecular subtypes into risk stratification ( Franco et al 2022 ).…”