THADA fusion 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 adenomaassociated (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. thyroid cancer | genetics | chromosomal rearrangements | IGF2BP3 | IGF1R

Genetic landscape of papillary thyroid carcinoma in the Chinese population

“…We also identified a novel THADA–IGF2BP3 gene fusion in PTC. During the evaluation of our manuscript, Panebianco et al reported the role of THADA–IGF2BP3 gene fusion in the carcinogenesis of PTC . However, our targeted RNA sequencing was not performed in patients with driver point mutations; therefore, potential novel gene fusions or novel isoforms of known fusions could be missed in them.…”

Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules

“…Each detected genetic alteration was annotated to receive a value of 0 to 2 based on the strength of its association with malignancy. The values were derived from 1) an extensive literature and searchable database review (eg, The Cancer Genome Atlas, cBioPortal, and the Catalogue of Somatic Mutations in Cancer), 2) an in‐house database of more than 1000 thyroid surgical and FNA samples with known surgical outcomes, 3) an RNA‐Seq analysis of thyroid cancer tissue and FNA samples, and 4) a CytoScan analysis of 17 thyroid cancer tissue samples. The total GC score for each sample was calculated as a sum of individual values of detected genomic alterations: where x is the weighted value (0‐2); n is the number of SNVs/indels; and SNV/I (single‐nucleotide variant/indel), GF, GEA, and CNA are indicators of the genomic alteration type.…”

“…Further enhancement of the diagnostic performance can be achieved by the expansion of existing tests and the incorporation of additional, more recently discovered molecular markers of thyroid cancer. Indeed, over the last several years, a number of new driver mutations and gene fusions (GFs) in different types of thyroid cancer have been discovered . Furthermore, it has been shown that a small but distinct proportion of thyroid cancers carry other types of molecular alterations, such as copy number variations .…”

“…Indeed, over the last several years, a number of new driver mutations and gene fusions (GFs) in different types of thyroid cancer have been discovered. [9][10][11][12][13] Furthermore, it has been shown that a small but distinct proportion of thyroid cancers carry other types of molecular alterations, such as copy number variations. 10,12 Importantly, the rapid development and improvement of sequencing assays allow the detection of multiple and various types of genetic alterations with a limited amount of cells collected by thyroid FNA.…”

Incremental utility of expanded mutation panel when used in combination with microRNA classification in indeterminate thyroid nodules

“…RAS mutations are the most common to indeterminate nodules and have been found in both benign and malignant nodules, presenting an uncertain PPV ranging from 15% to 70%. 28,[31][32][33][34][35][36][37][38][39][40][41][42] Furthermore, PPARG-and THADA-related fusion transcripts can have RAS-like properties, 15 while other fusions such as those related to NTRK and ALK have properties that are neither RAS-like nor BRAFV600E-like. Rare BRAF mutations, excluding BRAFV600E, have RAS-like properties rather than BRAFV600E-like properties, and have been found in both benign and malignant thyroid nodules.…”