Multilayer OMIC Data in Medullary Thyroid Carcinoma Identifies the STAT3 Pathway as a Potential Therapeutic Target inRETM918TTumors.
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 forRETM918T-related tumors. Integration of methylation data with mRNA and miRNA expression data identified genes negatively regulated by promoter methylation. Thesein silicofindings were confirmedin vitroforPLCB2, DKK4, MMP20, and miR-10a, -30a, and -200c. The mutation-specific aberrant methylation ofPLCB2, DKK4, andMMP20was validated in 25 independent MTCs by bisulfite pyrosequencing. The methylome and transcriptome data underscored JAK/Stat pathway involvement inRETM918TMTCs. 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 withRETM918T-bearing tumors (P< 0.02). Pharmacologic inhibition of STAT3 activity increased the sensitivity to vandetanib of theRETM918T-positive MTC cell line, MZ-CRC-1.Conclusions: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 ofRETM918TMTCs.Clin Cancer Res; 23(5); 1334-45. ©2016 AACR.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Veronika
V
Mancikova
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Cristina
C
Montero-Conde
Translational Bioinformatics Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Javier
J
Perales-Paton
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, University of Oviedo, Asturias, Spain.
Agustin
A
Fernandez
Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.
María
M
Santacana
DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Karolina
K
Jodkowska
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Lucia
L
Inglada-Pérez
Department of Endocrinology and Nutrition, Germans Trias i Pujol Hospital, Health Sciences Research Institute of the "Germans Trias i Pujol" Foundation (IGTP), Badalona, Spain.|Centre for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), ISCIII, Spain.
Esmeralda
E
Castelblanco
Hospital Virgen del Rocío, Sevilla.
Salud
S
Borrego
Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.
Mario
M
Encinas
Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.|Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, Barcelona.
Xavier
X
Matias-Guiu
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, University of Oviedo, Asturias, Spain.
Mario
M
Fraga
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. mrobledo@cnio.es.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Mercedes
M
Robledo
D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008297:Male; D009154:Mutation; D010880:Piperidines / Q000008:administration & dosage; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D010880:Piperidines; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib