Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours

Abstract

Chromosome 1p is frequently deleted in neuroblastoma (NB) tumours. The commonly deleted region has been narrowed down by loss of heterozygosity studies undertaken by different groups. Based on earlier mapping data, we have focused on a region on 1p36 (chr1: 7 765 595 -11 019 814) and performed an analysis of 30 genes by exploring features such as epigenetic regulation, that is DNA methylation and histone deacetylation, mutations at the DNA level and mRNA expression. Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs. Two patients with nonsynonymous mutations in the PIK3CD gene were detected. One patient harboured three variations in the same exon, and p.R188W. The other patient had the variation p.M655I. In addition, synonymous variations and one variation in an intronic sequence were also found. The mRNA expression of this gene is downregulated in unfavourable, compared to favourable, NBs. One nonsynonymous mutation was also identified in the ERRFI1 gene, p.N343S, and one synonymous. None of the variations above were found in healthy control individuals. In conclusion, of the 30 genes analysed, the PIK3CD gene stands out as one of the most interesting for further studies of NB development and progression.

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

“…2 Evidence indicates that the region between D1S508 and D1S244 markers on chr1p36 is one of the commonly deleted regions in NB. 3 There are 30 genes in this region and expression analysis of 4 of the 30 genes showed that two of them (CASZ1 and PIK3CD) are expressed at significantly lower levels in unfavorable NB as compared with favorable ones. 3 However, the tumor-suppressor functions of CASZ1 and PIK3CD have not been investigated.…”

“…3 There are 30 genes in this region and expression analysis of 4 of the 30 genes showed that two of them (CASZ1 and PIK3CD) are expressed at significantly lower levels in unfavorable NB as compared with favorable ones. 3 However, the tumor-suppressor functions of CASZ1 and PIK3CD have not been investigated. 3 CASZ1 maps to Chr1p36.22 and is a recently described zinc-finger (ZnF) transcription factor whose expression is upregulated during induction of NB and myoblast cell differentiation.…”

“…3 However, the tumor-suppressor functions of CASZ1 and PIK3CD have not been investigated. 3 CASZ1 maps to Chr1p36.22 and is a recently described zinc-finger (ZnF) transcription factor whose expression is upregulated during induction of NB and myoblast cell differentiation. 4 In Drosophila, the CASZ1 homolog, Drosophila castor (dcas), is expressed at a late stage of neuroblast development that precedes the cessation of proliferation and initiation of neuronal differentiation.…”

“…1 The finding that re-introduction of Chr1p into NB cells induces differentiation 11 supports the concept that loss of genes regulating developmental processes contributes to NB tumorigenicity. Developmentally regulated transcription factors are implicated in tumorigenesis in several pediatric tumors: MYCN in NB, [1][2][3][4] RB gene in retinoblastoma, 12 and REST/NRSF in medulloblastoma. 13 These transcription factors are also important regulators of signal transduction pathways that control developmental programs.…”

p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is overexpressed in tumors

“…In acute myeloid leukemia p110d is essential for PI3K activation and cell proliferation (Sujobert et al, 2005). The gene encoding p110d (PIK3CD) is also expressed in neuroblastoma , where it is occasionally mutated (Caren et al, 2007), and in breast cancer cells, where it stimulates chemotaxis in response to the epidermal growth factor (Sawyer et al, 2003). In contrast to the a-and b-isoforms of p110, the oncogenic activity of p110d is resistant to inhibitors of the MAP kinase pathway and does not require binding to RAS (Denley et al, 2008).…”