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Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Methyltransferase
Cell
030209 endocrinology & metabolism
Biology
medicine.disease_cause
lcsh:RC254-282
Article
03 medical and health sciences
Hürthle cell carcinoma
0302 clinical medicine
SOX2
SETD2
medicine
Thyroid cancer
Mutation
Thyroid
SETD2 loss-of-function mutations
poorly differentiated thyroid cancer
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
030104 developmental biology
medicine.anatomical_structure
Oncology
Cell culture
Cancer research
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....7248387271e8b76ff783ad891732dd4a
- Full Text :
- https://doi.org/10.3390/cancers12071892