(A) Adult and pediatric thyroid cancers are categorized according to different molecular subgroups. TCGA generated a two-tiered classification (BRAF-like vs. RAS-like) in adult PTC, with BRAF-like tumors having a higher ERK score, a lower TDS, and an increased risk for invasive behavior compared with RAS-like tumors. Data from Y.A. Lee, H. Lee, and colleagues (14) show that pediatric tumors harboring kinase fusion oncogenes followed a pattern similar to that seen in adult PTCs with BRAF. Combined with previously published data, a three-tier classification system in pediatric PTC may more accurately correlate with clinical behavior. A three-tiered system would encompass RAS-like, BRAF-like, and fusion-like PTCs and thus reflect an increasing risk of invasive behavior. (B) In adult and pediatric thyroid cancer, signaling pathways are associated with loss of differentiation. In adults, PTCs with a BRAF mutation (and MAPK activation) are associated with a lower TDS (left). In pediatric tumors, PTCs with kinase fusion oncogenes are associated with a lower TDS. The use of MAPK inhibitors to specifically block the oncogenes in these tumors reduces ERK activation and restores the expression of differentiation genes, including the gene that encodes NIS, which correlates with a response to RAI therapy. (C) In pediatric PTC cells, exposure to an oncogene-specific inhibitor results in increased expression of NIS on the basolateral membrane, which sensitizes the cells to RAI.