title: DNA methylation profiling of well-differentiated thyroid cancer uncovers markers of recurrence free survival.
abstract: Thyroid cancer is a heterogeneous disease with several subtypes characterized by cytological, histological and genetic alterations, but the involvement of epigenetics is not well understood. Here, we investigated the role of aberrant DNA methylation in the development of well-differentiated thyroid tumors. We performed genome-wide DNA methylation profiling in the largest well-differentiated thyroid tumor series reported to date, comprising 83 primary tumors as well as 8 samples of adjacent normal tissue. The epigenetic profiles were closely related to not only tumor histology but also the underlying driver mutation; we found that follicular tumors had higher levels of methylation, which seemed to accumulate in a progressive manner along the tumorigenic process from adenomas to carcinomas. Furthermore, tumors harboring a BRAF or RAS mutation had a larger number of hypo- or hypermethylation events, respectively. The aberrant methylation of several candidate genes potentially related to thyroid carcinogenesis was validated in an independent series of 52 samples. Furthermore, through the integration of methylation and transcriptional expression data, we identified genes whose expression is associated with the methylation status of their promoters. Finally, by integrating clinical follow-up information with methylation levels we propose etoposide-induced 2.4 and Wilms tumor 1 as novel prognostic markers related to recurrence-free survival. This comprehensive study provides insights into the role of DNA methylation in well-differentiated thyroid cancer development 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.forename: Raquel
authors.initials: R
authors.lastname: Buj
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Castelblanco
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Anna
authors.initials: A
authors.lastname: Diez
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Maria
authors.initials: M
authors.lastname: Curras-Freixes
authors.forename: Francisco Xavier
authors.initials: FX
authors.lastname: Maravall
authors.forename: Didac
authors.initials: D
authors.lastname: Mauricio
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Manel
authors.initials: M
authors.lastname: Puig-Domingo
authors.forename: Ismael
authors.initials: I
authors.lastname: Capel
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Bella
authors.forename: Enrique
authors.initials: E
authors.lastname: Lerma
authors.forename: Eva
authors.initials: E
authors.lastname: Castella
authors.forename: Jordi Lluis
authors.initials: JL
authors.lastname: Reverter
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Peinado
authors.forename: Mireia
authors.initials: M
authors.lastname: Jorda
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016172:DNA Fingerprinting; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015996:Survival Rate; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D025721:WT1 Proteins / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D025721:WT1 Proteins; C583751:WT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
keywords: BRAF; RAS; methylation; prognostic markers; well-differentiated thyroid cancer