title: GSTP1 hypermethylation is associated with reduced protein expression, aggressive disease and prognosis in neuroblastoma.
abstract: Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup.
authors: Department of Pediatrics, University Hospital of Geneva, Switzerland. fabienne.gumypause@unige.ch
authors: Fabienne
authors: F
authors: Gumy-Pause
authors: Bruno
authors: B
authors: Pardo
authors: Mary
authors: M
authors: Khoshbeen-Boudal
authors: Marc
authors: M
authors: Ansari
authors: Angèle
authors: A
authors: Gayet-Ageron
authors: André-Pascal
authors: AP
authors: Sappino
authors: Edward F
authors: EF
authors: Attiyeh
authors: Hulya
authors: H
authors: Ozsahin
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D015536:Down-Regulation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D051549:Glutathione S-Transferase pi / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D014408:Biomarkers, Tumor; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi