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Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma

Artikel i vetenskaplig tidskrift
Författare Helena Carén
Anna Djos
Maria Nethander
Rose-Marie Sjöberg
Per Kogner
Camilla Enström
Staffan Nilsson
Tommy Martinsson
Publicerad i BMC Cancer
Volym 11
ISSN 1471-2407
Publiceringsår 2011
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Institutionen för matematiska vetenskaper, matematisk statistik
Språk en
Länkar hdl.handle.net/2077/24870
https://gup.ub.gu.se/file/59243
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

Background Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes. Methods In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation. Results We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p < 0.001), PRKCDBP (p < 0.001) and KRT19 (p < 0.01). Among these, the mRNA expression of KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP). Conclusions In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas.

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