2026-04-29T06:15:50Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/272072026-02-07T01:16:08Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Mancikova, Veronika
author
Montero-Conde, Cristina
author
Perales-Paton, Javier
author
Fernandez, Agustin
author
Santacana, María
author
Jodkowska, Karolina
author
Inglada-Pérez, Lucia
author
Castelblanco, Esmeralda
author
Borrego, Salud
author
Encinas, Mario
author
Matias-Guiu, Xavier
author
Fraga, Mario
author
Robledo Batanero, Mercedes
funder
European Union (EU)
funder
Instituto de Salud Carlos III
funder
Comunidad de Madrid
funder
Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)
funder
AECC
funder
LA CAIXA
2026-02-06T17:37:03Z
2026-02-06T17:37:03Z
2017-03-01
https://hdl.handle.net/20.500.12105/27207
27620278
CLINICAL CANCER RESEARCH
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. 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. The most distinctive methylome was observed for -related tumors. Integration of methylation data with mRNA and miRNA expression data identified genes negatively regulated by promoter methylation. These findings were confirmed for , and miR-10a, -30a, and -200c. The mutation-specific aberrant methylation of , and was validated in 25 independent MTCs by bisulfite pyrosequencing. The methylome and transcriptome data underscored JAK/Stat pathway involvement in 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 -bearing tumors ( < 0.02). Pharmacologic inhibition of STAT3 activity increased the sensitivity to vandetanib of the -positive MTC cell line, MZ-CRC-1. Multilayer OMIC data analysis uncovered methylation hallmarks in genetically defined MTCs and revealed JAK/Stat signaling effector STAT3 as a potential therapeutic target for the treatment of MTCs. .
eng
DNA METHYLATION
CANCER-CELLS
GENE-EXPRESSION
PROGNOSTIC-SIGNIFICANCE
RET PROTOONCOGENE
TYROSINE KINASE
BREAST CANCER
SOLID TUMORS
MUTATIONS
GROWTH
Multilayer OMIC Data in Medullary Thyroid Carcinoma Identifies the STAT3 Pathway as a Potential Therapeutic Target in Tumors.
research article
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