Back to Search Start Over

Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid

Authors :
Giorgio Grani
Cosimo Durante
Rosa Falcone
Cira Di Gioia
Marialuisa Sponziello
Antonella Verrienti
Valeria Ramundo
Diego Russo
Sebastiano Filetti
Valeria Pecce
Raffaella Carletti
Luana Abballe
Source :
Cancers, Vol 12, Iss 1892, p 1892 (2020), Cancers, Volume 12, Issue 7
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

H&uuml<br />rthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study.

Details

ISSN :
20726694
Volume :
12
Database :
OpenAIRE
Journal :
Cancers
Accession number :
edsair.doi.dedup.....7248387271e8b76ff783ad891732dd4a
Full Text :
https://doi.org/10.3390/cancers12071892