Abstract
Retinoblastoma is rare tumor of the retina caused by the homozygous loss of the Retinoblastoma 1 tumor suppressor gene (RB1). Loss of the RB1 protein, pRB, results in de-regulated activity of the E2F transcription factors, chromatin changes and developmental defects leading to tumor development. Extensive microarray profiles of these tumors have enabled the identification of genes sensitive to pRB disruption, however, this technology has a number of limitations in the RNA profiles that they generate. The advent of RNA-sequencing has enabled the global profiling of all of the RNA within the cell including both coding and non-coding features and the detection of aberrant RNA processing events. In this perspective, we focus on discussing how RNA-sequencing of rare Retinoblastoma tumors will build on existing data and open up new area’s to improve our understanding of the biology of these tumors. In particular, we discuss how the RB-research field may be to use this data to determine how RB1 loss results in the expression of; non-coding RNAs, causes aberrant RNA processing events and how a deeper analysis of metabolic RNA changes can be utilized to model tumor specific shifts in metabolism. Each section discusses new opportunities and challenges associated with these types of analyses and aims to provide an honest assessment of how understanding these different processes may contribute to the treatment of Retinoblastoma.
Highlights
Tight control over proliferation and differentiation processes are fundamentally important to modulating organismal development and prevent oncogenic growth
The Retinoblastoma 1 (Rb1: gene, pRB: protein) gene and the E2 promoter binding Factors (E2Fs) function to control both of these pathways (Hiebert et al, 1992; Du et al, 1996)
In cancer cells the pRB pathway is disabled by numerous mechanisms including; inactivating and/or gene mutations with in the Rb1 loci (Friend et al, 1986), the E7 oncoprotein produced by the Human Papilloma Virus (Dyson et al, 1989), the amplification or overexpression Cyclin D and/or Cyclin Dependent Kinase 4 or 6 (CDK4 and CDK6) (Nobori et al, 1994; Connell-Crowley et al, 1997; Harbour et al, 1999) or by the deletion or silencing of CDK inhibitors, CDKN2A-D (Cairns et al, 1994)
Summary
The advent of RNA-sequencing has enabled the global profiling of all of the RNA within the cell including both coding and non-coding features and the detection of aberrant RNA processing events. In this perspective, we focus on discussing how RNA-sequencing of rare Retinoblastoma tumors will build on existing data and open up new area’s to improve our understanding of the biology of these tumors. We discuss how the RB-research field may be to use this data to determine how RB1 loss results in the expression of; non-coding RNAs, causes aberrant RNA processing events and how a deeper analysis of metabolic RNA changes can be utilized to model tumor specific shifts in metabolism.
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