RT Journal Article
T1 Multilayer OMIC Data in Medullary Thyroid Carcinoma Identifies the STAT3 Pathway as a Potential Therapeutic Target in RETM918T Tumors.
A1 Mancikova, Veronika
A1 Montero-Conde, Cristina
A1 Perales-Paton, Javier
A1 Fernandez, Agustin
A1 Santacana, María
A1 Jodkowska, Karolina
A1 Inglada-Pérez, Lucia
A1 Castelblanco, Esmeralda
A1 Borrego, Salud
A1 Encinas, Mario
A1 Matias-Guiu, Xavier
A1 Fraga, Mario
A1 Robledo, Mercedes
AB Purpose: Medullary thyroid carcinoma (MTC) is a rare disease with few genetic drivers, and the etiology specific to each known susceptibility mutation remains unknown. Exploiting multilayer genomic data, we focused our interest on the role of aberrant DNA methylation in MTC development.Experimental Design: We performed genome-wide DNA methylation profiling assessing more than 27,000 CpGs in the largest MTC series reported to date, comprising 48 molecularly characterized tumors. mRNA and miRNA expression data were available for 33 and 31 tumors, respectively. Two human MTC cell lines and 101 paraffin-embedded MTCs were used for validation.Results: The most distinctive methylome was observed for RETM918T-related tumors. Integration of methylation data with mRNA and miRNA expression data identified genes negatively regulated by promoter methylation. These in silico findings were confirmed in vitro for PLCB2, DKK4, MMP20, and miR-10a, -30a, and -200c. The mutation-specific aberrant methylation of PLCB2, DKK4, and MMP20 was validated in 25 independent MTCs by bisulfite pyrosequencing. The methylome and transcriptome data underscored JAK/Stat pathway involvement in RETM918T MTCs. Immunostaining [immunohistochemistry (IHC)] for the active form of signaling effector STAT3 was performed in a series of 101 MTCs. As expected, positive IHC was associated with RETM918T-bearing tumors (P
YR 2016
FD 2016-09-12
LK http://hdl.handle.net/10668/10437
UL http://hdl.handle.net/10668/10437
LA en
DS RISalud
RD Apr 5, 2025