title: MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors.
abstract: MicroRNA deregulation could be a crucial event in thyroid carcinogenesis. However, current knowledge is based on studies that have used inherently biased methods. Thus, we aimed to define in an unbiased way a list of deregulated microRNAs in well-differentiated thyroid cancer in order to identify diagnostic and prognostic markers. We performed a microRNA deep-sequencing study using the largest well-differentiated thyroid tumor collection reported to date, comprising 127 molecularly characterized tumors with follicular or papillary patterns of growth and available clinical follow-up data, and 17 normal tissue samples. Furthermore, we integrated microRNA and gene expression data for the same tumors to propose targets for the novel molecules identified. Two main microRNA expression profiles were identified: one common for follicular-pattern tumors, and a second for papillary tumors. Follicular tumors showed a notable overexpression of several members of miR-515 family, and downregulation of the novel microRNA miR-1247. Among papillary tumors, top upregulated microRNAs were miR-146b and the miR-221~222 cluster, while miR-1179 was downregulated. BRAF-positive samples displayed extreme downregulation of miR-7 and -204. The identification of the predicted targets for the novel molecules gave insights into the proliferative potential of the transformed follicular cell. Finally, by integrating clinical follow-up information with microRNA expression, we propose a prediction model for disease relapse based on expression of two miRNAs (miR-192 and let-7a) and several other clinicopathological features. This comprehensive study complements the existing knowledge about deregulated microRNAs in the development of well-differentiated thyroid cancer and identifies novel markers associated with recurrence-free survival.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Veronika
authors.initials: V
authors.lastname: Mancikova
authors.affiliation: Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Castelblanco
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Pineiro-Yanez
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Perales-Paton
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Perez
authors.affiliation: Department of Pathology, University Hospital Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Department of Endocrinology and Nutrition, Hospital de Sabadell, Sabadell, Barcelona, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Capel
authors.affiliation: Department of Pathology, Hospital de Sabadell, Sabadell, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Bella
authors.affiliation: Department of Pathology, Hospital Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lerma
authors.affiliation: 1] Instituto de Investigaciones Biomedicas 'Alberto Sols', Madrid, Spain [2] Hospital Universitario de Mostoles, Móstoles, Madrid, Spain.
authors.forename: Garcilaso
authors.initials: G
authors.lastname: Riesco-Eizaguirre
authors.affiliation: Instituto de Investigaciones Biomedicas 'Alberto Sols', Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
authors.affiliation: Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA, Lleida, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Maravall
authors.affiliation: 1] Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Spain [2] Department of Endocrinology and Nutrition, University Hospital Germans Trias i Pujol, Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Didac
authors.initials: D
authors.lastname: Mauricio
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000401:mortality; D000293:Adolescent; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality; D002291:Carcinoma, Papillary; D016000:Cluster Analysis; D018572:Disease-Free Survival; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016016:Proportional Hazards Models; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality; D059467:Transcriptome; D055815:Young Adult
chemical_list: D035683:MicroRNAs