Epigenetic silencing of the tumor suppressor genesSPI1, PRDX2, KLF4, DLEC1, andDAPK1in childhood and adolescent lymphomas

Abstract

The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas.

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

“…It is important to clarify that the epigenome plays a role in the two-hit hypothesis either on its own (with evidence to support the role of DNA methylation as the second hit ( 101 )) or by exerting its effect on tumour suppressor genes through the process of epigenetic silencing ( 102 ). Our hypothesis presented in this manuscript thus represents a variation from the long-held dogmas of carcinogenesis, namely, the inherited genetic susceptibility and acquired two-hit hypothesis (of Knudson) ( 18 ).…”

KLF4, DAPK1 and SPG20 promoter methylation is not affected by DNMT1 silencing and hypomethylating drugs in lymphoma cells

“…DAPK1 plays a role in lymphomas, as recently demonstrated by a meta-analysis where hypermethylation of the promoter was found to be associated with the 5-year survival rate of patients ( 8 , 9 ). Overall, DAPK1 hypermethylation corresponds to a significantly lower survival and represents an independent, negative prognostic biomarker ( 8 ).…”

“…Hypermethylated KLF4 has also been associated with the poor prognosis of patients with splenic marginal zone lymphomas (SMZL) and SMZL cell lines exposed to hypomethylating agents show a reduced proliferation (6,7). DAPK1 plays a role in lymphomas, as recently demonstrated by a meta-analysis where hypermethylation of the promoter was found to be associated with the 5-year survival rate of patients (8,9). Overall, DAPK1 hypermethylation corresponds to a significantly lower survival and represents an independent, negative prognostic biomarker (8).…”

Expression of Oncogenic Molecules in Pediatric Ulcerative Colitis

“…These findings suggest that improving chronic inflammation of the gastrointestinal mucosa is an important factor for reducing carcinogenesis risk. SPI1 encodes a transcription factor that activates the expression of genes involved in cell proliferation in bone marrow [21] and is reportedly a poor prognostic biomarker for childhood T-cell acute lymphoblastic leukemia [22,23]. SPI1 is also involved in T-cell biology and is reportedly associated with regulatory T cells, UC, colorectal cancer, and colitis-associated cancer [24][25][26].…”