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

Cancers
Valeria PecceMarialuisa Sponziello

Abstract

Hürthle 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.

References

Aug 22, 2003·Thyroid : Official Journal of the American Thyroid Association·Nikola BesicMarija Auersperg
Nov 2, 2004·World Journal of Surgery·Yevgeniya KushchayevaOrlo H Clark
Mar 22, 2008·The Journal of Urology·Lakshmipathi KhandrikaHari K Koul
Apr 4, 2008·Proceedings of the National Academy of Sciences of the United States of America·Yong-Jig Cho, Peng Liang
Oct 6, 2010·Biochemical and Biophysical Research Communications·Sanna BarrandPhilippe Collas
Apr 20, 2012·Endocrine-related Cancer·Valdemar MáximoManuel Sobrinho-Simões
Jan 18, 2013·Nucleic Acids Research·Sílvia CarvalhoSérgio Fernandes de Almeida
Apr 27, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·A Ari HakimiUNKNOWN ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators
Sep 16, 2015·Endocrine·Mariavittoria DimaCosimo Durante
Nov 26, 2015·Cancer Cell·Sophia X PfisterTimothy C Humphrey
Feb 16, 2016·The Journal of Clinical Investigation·Iñigo LandaJames A Fagin
Jul 13, 2016·Endocrine-related Cancer·Antonella VerrientiCosimo Durante
Aug 23, 2016·Future Medicinal Chemistry·David S RogawskiTomasz Cierpicki
Sep 15, 2016·The New England Journal of Medicine·James A Fagin, Samuel A Wells
Feb 6, 2017·Cold Spring Harbor Perspectives in Medicine·Catherine C Fahey, Ian J Davis
Nov 6, 2017·The Lancet. Diabetes & Endocrinology·Giorgio GraniDavid S Cooper
Mar 25, 2018·Cell Research·Mrinal M Patnaik, Omar Abdel-Wahab

❮ Previous
Next ❯

Citations

Jun 29, 2021·Frontiers in Endocrinology·David G McFadden, Peter M Sadow
Jul 21, 2021·Scientific Reports·Valeria PeccePaola Paci

❮ Previous
Next ❯

Methods Mentioned

BETA
dissection
Antibody Array
transfection

Clinical Trials Mentioned

NCT01748825

Software Mentioned

Torrent Suite
Ion Reporter
Ion GeneStudio S5 system
wANNOVAR
GraphPad Prism
Oncoarray
ClinVar
GraphPad

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.