Abstract
Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in ∼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit.
Keywords:
IGF1R; IGF2BP3; chromosomal rearrangements; genetics; thyroid cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Transformation, Neoplastic
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Female
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Gene Expression Regulation, Neoplastic*
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Genetic Loci
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Genome-Wide Association Study
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Humans
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Imidazoles / pharmacology
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Biosynthesis
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Protein Kinase Inhibitors / pharmacology
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Pyrazines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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Receptor, IGF Type 1
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Receptors, Somatomedin / antagonists & inhibitors
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Receptors, Somatomedin / genetics*
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Receptors, Somatomedin / metabolism
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Signal Transduction
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Thyroid Neoplasms / drug therapy
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Thyroid Neoplasms / genetics*
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
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Antineoplastic Agents
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IGF1R protein, human
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IGF2 protein, human
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IGF2BP3 protein, human
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Imidazoles
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Protein Kinase Inhibitors
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Pyrazines
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RNA, Messenger
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RNA-Binding Proteins
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Receptors, Somatomedin
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THADA protein, human
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Insulin-Like Growth Factor II
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Receptor, IGF Type 1
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Mitogen-Activated Protein Kinases