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: Veronika Mancikova, Raquel Buj, Esmeralda Castelblanco, Lucía Inglada-Pérez, Anna Diez, Aguirre A de Cubas, Maria Curras-Freixes, Francisco Xavier Maravall, Didac Mauricio, Xavier Matias-Guiu, Manel Puig-Domingo, Ismael Capel, María Rosa Bella, Enrique Lerma, Eva Castella, Jordi Lluis Reverter, Miguel Ángel Peinado, Mireia Jorda, Mercedes Robledo
• Journal: International journal of cancer (Int J Cancer) Vol. 135 Issue 3 Pg. 598-610 (Aug 01 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24382797 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 UICC.

Chemical References

• Biomarkers, Tumor
• WT1 Proteins
• WT1 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• ras Proteins

Topics

• Adenoma (genetics, mortality, pathology)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics)
• Carcinoma, Papillary (genetics, mortality, pathology)
• DNA Fingerprinting
• DNA Methylation
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Recurrence, Local (genetics, mortality, pathology)
• Neoplasm Staging
• Prognosis
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Survival Rate
• Thyroid Gland (metabolism)
• Thyroid Neoplasms (genetics, mortality, pathology)
• WT1 Proteins (genetics)
• Young Adult
• ras Proteins (genetics)