Mutational analysis using next generation sequencing in pediatric thyroid cancer reveals BRAF and fusion oncogenes are common.

BACKGROUND: We previously described mutation rates of BRAFV600E, RAS, RET-PTC and PAX8-PPARγ in pediatric subjects with well-differentiated thyroid cancer (WDTC). We expanded the cohort adding next-generation sequencing (NGS) and assessed genotype-phenotype correlations. METHODS: Single-center retrospective cohort examining thyroidectomy tissue blocks from consecutive pediatric WDTC patients between 2001 and 2015. Tissues were analyzed at Quest Diagnostics for BRAF, RAS mutations, RET-PTC and PAX8-PPARγ, and additional fusions, using standalone and NGS tests. WDTC included papillary (PTC), follicular (FTC) and follicular-variant PTC (FVPTC). RESULTS: We genotyped 46 samples (36 females). Mean age at diagnosis was 14.7 years and the cohort comprised of mostly Hispanic (60.9%) and Caucasian (26.1%) patients. Mean follow-up was 3.5 years. Genetic alterations (GA) were noted in 69.6%, with BRAFV600E (n = 11), and RET-PTC (n = 8) detected only in PTC. GA were detected in 2/7 FTC (1 PAX8-PPARγ, 1 NRAS) and 6/10 FVPTC (3 PAX8-PPARγ, 1 STRN-ALK, 1 BRAFK601E, 1 NRAS). Patients with BRAFV600E were predominantly Hispanic (81.8%) and >15 years (81.8%), whereas 87.5% RET-PTC and 50% other-fusions occurred in patients ≤15 years (p = 0.044). Of the 29 PTC patients, 82.8% had GA: BRAFV600E (37.9%), RET-PTC (27.6%), 17.2% other fusion-oncogenes (2 -ALK, 3 -NTRK). Non-RET fusions had the highest vascular invasion (100%, p = 0.042 vs RET-PTC) and frequent lymphatic invasion (80%). GA were most common in PTC with cervical metastasis. CONCLUSIONS: BRAFV600E was the most common single mutation, especially in older and Hispanic adolescents. All fusions combined are more common than BRAFV600E. NGS reveals a genetic basis in most pediatric WDTC, which may have implications for the role of molecular testing and systemic therapy.