title: DNA hypomethylation affects cancer-related biological functions and genes relevant in neuroblastoma pathogenesis.
abstract: Neuroblastoma (NB) pathogenesis has been reported to be closely associated with numerous genetic alterations. However, underlying DNA methylation patterns have not been extensively studied in this developmental malignancy. Here, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. Stringent supervised differential methylation analyses allowed us to identify epigenetic changes characteristic for NB tumors as well as for clinical and biological subtypes of NB. We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. Remarkably, such hypomethylation affected cancer-related biological functions and genes relevant to NB pathogenesis such as CCND1, SPRR3, BTC, EGF and FGF6. In particular, differential methylation in CCND1 affected mostly an evolutionary conserved functionally relevant 3' untranslated region, suggesting that hypomethylation outside promoter regions may play a role in NB pathogenesis. Hypermethylation targeted genes involved in cell development and proliferation such as RASSF1A, POU2F2 or HOXD3, among others. The results derived from this study provide new candidate epigenetic biomarkers associated with NB as well as insights into the molecular pathogenesis of this tumor, which involves a marked gene-specific hypomethylation.
authors.affiliation: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Mayol
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: José
authors.initials: J
authors.lastname: Ríos
authors.forename: Ana
authors.initials: A
authors.lastname: Queiros
authors.forename: Marta
authors.initials: M
authors.lastname: Kulis
authors.forename: Mariona
authors.initials: M
authors.lastname: Suñol
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Soledad
authors.initials: S
authors.lastname: Gómez
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.forename: Carmen
authors.initials: C
authors.lastname: de Torres
authors.forename: Eva
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Patricia
authors.initials: P
authors.lastname: Galván
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lavarino
mesh_terms: D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009447:Neuroblastoma / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D013696:Temperature
chemical_list: C530104:CCND1 protein, human; D019938:Cyclin D1