High levels of global genome methylation in patients with retinoblastoma

Abstract

Retinoblastoma is a tumor of the embryonic neural retina in young children. The DNA methyltransferase 1 (DNMT1) gene has been demonstrated to be transcriptionally activated in cells lacking retinoblastoma 1 (RB1). Thus, there is a direct interaction between DNMT1 and RB1 in vivo. The present study hypothesized that uncontrolled DNMT1, DNMT2 and DNMT3 expression may lead to a high level of global genome methylation causing a second hit or where both alleles are altered, in RB1 and/or inactivation of other genes in retinal cells. To test this, the global genome methylation levels were analyzed in 69 patients with retinoblastoma, as well as 26 healthy siblings and 18 healthy unrelated children as the control groups. Peripheral blood and tumor tissue samples were obtained from 32 patients. The expression levels of DNMT genes were also determined in cell lines. Based on the median levels of global genome methylation in patients, higher genome-wide methylation levels in peripheral blood were associated with a 3.33-fold increased risk for retinoblastoma in patients compared with all healthy controls (95% confidence interval, 0.98-11.35; P<0.0001). The level of global genome methylation and the expression of DNMT genes were increased in the WERI-RB-1 cell line, which has a mutated RB1 gene, compared with a wild-type RB1-expressing cell line. These results supported the hypothesis that epigenetic alterations, as well as mutations in RB1, may be associated with the oncogenesis and inheritance of retinoblastoma. The repression of genes that interact with RB1, such as the DNMT gene family, may be important in patients with retinoblastoma with alterations in RB1, and may serve a role in the treatment and regression of retinoblastoma.

Molecular Changes in Retinoblastoma beyond RB1: Findings from Next-Generation Sequencing

“…Future studies may expand upon these results by considering more downstream analytes, such as DNA methylation or RNA expression, to assess biological differences between patients either dependent or independent of DNA mutations. For example, recent studies have considered genome-wide methylation and found expression patterns unique to retinoblastoma, suggesting their importance to oncogenesis [ 40 , 41 ]. Further clinical assessment of patient phenotypes alongside various biological measurements may yield important insight into the progression of retinoblastoma from DNA mutation to unique clinicopathological features of retinoblastoma.…”

Cell-molecular mechanisms of progression of ophthalmological pathology on the background of influence of environmental factors. Literature review

“…In normal cells of the human body, the level of MGMT expression depends on their type, it is not stable and varies in different individuals. Regulation of MGMT gene expression is carried out by various intracellular systems, including and p53 protein-mediated [10]. Especially low expression of reparative enzyme in brain tissues [11].…”

Valproate Targets Mammalian Gastrulation Impairing Neural Tissue Differentiation and Development of the Placental Source In Vitro

“…However, it is possible that HDACi, through enhanced P21 gene and p21 protein expression, also enhanced pRb dephosphorylation that blocks the cell cycle, as shown previously [ 44 ]. Inactivation of the retinoblastoma gene has recently been associated with high levels of global DNA methylation [ 45 ], while histone acetylation by an HDACi could induce DNA demethylation [ 46 ]. However, we did not assess any global DNA-methylation changes in VPA-treated embryos compared to controls.…”