THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer

Significance Thyroid cancer is the fastest-growing cancer type in the United States, yet its molecular mechanisms are not fully understood. Here we report the identification and characterization of a gene fusion involving the thyroid adenoma-associated ( THADA ) and LOC389473 genes in papillary thyroid cancers, which leads to strong overexpression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and signaling via the IGF2/IGF1 receptor (IGF1R) pathway. As a result, we report a previously unknown structural mechanism responsible for IGF2BP3 overexpression in cancer. We also show that IGF2BP3 overexpression via different mechanisms can be found in 5 to 15% of several cancer types, and demonstrate that growth of these tumors can be blocked by IGF1R inhibitors. This raises the possibility that IGF2BP3 overexpression may be used to predict therapeutic response to IGF1R inhibition in cancer cells.