title: THADAfusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer.
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 theLOC389473gene on chromosome 7 located 12 kb upstream of theIGF2BP3gene. We show thatTHADAfusion toLOC389473and 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.THADAfusions 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Federica
authors.initials: F
authors.lastname: Panebianco
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Kelly
authors.affiliation: Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Sanja
authors.initials: S
authors.lastname: Dacic
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Aatur D
authors.initials: AD
authors.lastname: Singhi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Dhir
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Shih-Fan
authors.initials: SF
authors.lastname: Kuan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: David
authors.initials: D
authors.lastname: Dabbs
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Affymetrix, Inc., Santa Clara, CA 95051.
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.affiliation: Affymetrix, Inc., Santa Clara, CA 95051.
authors.forename: Rachel
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Abigail I
authors.initials: AI
authors.lastname: Wald
authors.affiliation: Division of Endocrine Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Carty
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; nikiforovye@upmc.edu.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007335:Insulin-Like Growth Factor II; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; C498780:IGF2BP3 protein, human; C477698:THADA protein, human
keywords: IGF1R; IGF2BP3; chromosomal rearrangements; genetics; thyroid cancer