Institute of Predictive and Personalized Medicine of Cancer IMPPC Barcelona

Badalona, Spain

Institute of Predictive and Personalized Medicine of Cancer IMPPC Barcelona

Badalona, Spain

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Mancikova V.,Hereditary Endocrine Cancer Group | Buj R.,Institute of Predictive and Personalized Medicine of Cancer IMPPC Barcelona | Castelblanco E.,University of Lleida | Castelblanco E.,Center for Biomedical Research on Rare Diseases | And 20 more authors.
International Journal of Cancer | Year: 2014

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. What's new? Follicular cell-derived carcinomas of the thyroid gland, which are the most common endocrine malignancies, are of special interest for molecular research, given their common cellular origin. However, whether epigenetic modifications contribute to the heterogeneous nature of follicular thyroid malignancies remains unclear. Here, genome-wide characterization of DNA methylation patterns of well-differentiated thyroid tumors shows that tumors with distinct subtypes and mutational status have unique methylation profiles, offering insight into the biology underlying the heterogeneity and differential outcomes of thyroid cancers. Novel markers associated with recurrence-free survival were also identified and could be used for patient classification. © 2013 UICC.


PubMed | Advanced Personalized Diagnostics, University of Extremadura, Vall dHebron Research Institute VHIR Barcelona, Institute of Predictive and Personalized Medicine of Cancer IMPPC Barcelona and 3 more.
Type: Journal Article | Journal: Molecular genetics & genomic medicine | Year: 2015

Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.

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