IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis

Abstract

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6–5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8–7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

The MicroRNA Landscape of MYCN-Amplified Neuroblastoma

“…On the contrary, IGF2BP1 upregulation in MNA neuroblastoma is supported by previous studies in primary tumors, MYC/MYCN-driven transcriptional regulation and conserved oncofetal expression of the protein (13,14,46,47). Notably in this respect, the conserved upregulation or de novo synthesis of IGF2BP1 in cancer is primarily observed in progressed, de-differentiated malignancies, as demonstrated for instance in anaplastic thyroid carcinoma (48). MYCN-3'UTR reporter studies provide strong evidence that both proteins modulate MYCN expression in a 3'UTR-dependent manner.…”

Characterizing dedifferentiation of thyroid cancer by integrated analysis

“…The impact of CREB3L1 on ATC development was further evaluated by GSEA on bulk RNA expression data from four independent publicly accessible thyroid cancer studies [accession GSE33630 ( 17 ), GSE27155 ( 27 ), GSE65144 ( 28 ), and GSE126698 ( 29 )]. Consistently, expression of CREB3L1 and genes involved in EMT/mTORC1 pathways was significantly enriched in ATC compared with normal samples ( Fig.…”

MSI1 Promotes the Expression of the GBM Stem Cell Marker CD44 by Impairing miRNA-Dependent Degradation

“…In support of the MSI1-directed control of CD44 mRNA abundance and turnover, we demonstrate that MSI1 promotes CD44 mRNA stability, the activity of luciferase reporters harboring the CD44-3 UTR as well as abundance of the endogenous mRNA in a 3 UTR-dependent manner. This regulation is reminiscent of regulation by another oncofetal RBP, the IGF2 mRNA-binding protein 1 (IGF2BP1), which is highly expressed in aggressive malignancies [46,47]. This promotes stemness properties in cancer cells by impairing the miRNA-dependent downregulation of target mRNAs after recruiting the respective mRNAs to miRNA/RISC-devoid mRNPs [14,40,47,48].…”