Tumorigenesis in retinoblastoma

Retinoblastoma is a rare type of eye cancer that affects young children, most of whom are usually under five years of age. The condition can affect either both eyes (bilateral retinoblastoma) or just one (unilateral retinoblastoma), with usually a much earlier diagnosis if both eyes are affected. If it is diagnosed at an early stage, survival rates for children are over 95%. There are two types of retinoblastoma, genetic (about 45% of affected children have this) and non-genetic.

Retinoblastoma develops due to the formation of a cancerous tumor. The formation of this tumor is a process called tumorigenesis. Tumorigenesis has been widely accepted as a multistep process which involves an accumulation of mutations within tissue cells. Mutations result in problems with tissue homeostasis as the mutated cells gain strength by increasing their proliferation rate, decreasing their death rate, and creating a growth-promoting environment.

Retinoblastoma has been found to be caused by mutations in the RB1 gene, which is a tumor suppressor. This tumor supressing gene involved with retinoblastoma was actually the first ever tumor suppressor gene to be identified. The tumor suppressing role of the RB1 gene has been found not to be located in just the retina in retinoblastoma, as sporadic somatic mutations in the RB1 gene have been found in several other cancers. This gene has diverse cellular functions ranging from antiapoptosis and differentiation to regulation of the cell cycle, DNA-damage responses, DNA repair, and DNA replication. All of these properties may contribute to its function as a tumor suppressor, and retinoblastoma can develop when the tumor suppressing gene is made defective by a mutation. Susceptibility to retinoblastoma is transmitted as a dominant trait, with approximately 50% of the children of an affected parent developing it. However, it has been found that inheritance of the susceptibility gene alone is insufficient to cause tumorigenesis and lead to the development of retinoblastoma. In 1971, Alfred Knudson proposed that for retinoblastoma to develop, two mutations are required, involving the loss of both of the functional copies of the tumor susceptibility gene (the RB1 tumor suppressor gene) that would be present on homologous chromosomes of a normal diploid cell. With inherited retinoblastoma, one defective copy of the RB1 gene is genetically transmitted. The loss of this single copy however is insufficient to lead to the development of a tumor. In order for tumorigenesis to occur, both copies of the RB1 gene need to be defective, so a tumor only arises when a second somatic mutation occurs, leading to the loss of the remaining normal RB1 allele.

In January 2009 the findings of an investigation into the microRNAs associated with tumorigenesis of retinoblastoma were published in a scientific journal. The researchers used a process called microRNA microarray technique to identify the microRNA present in retinoblastoma, and It was found that a cluster of microRNAs were identified as highly expressed, including hsa-miR-494, hsa-let-7e, hsa-miR-513–1, hsa-miR-513–2, hsa-miR-518c, hsa-miR-129–1, hsa-miR-129–2, hsa-miR-198, hsa-miR-492, hsa-miR-498, hsa-miR-320, hsa-miR-503, and hsa-miR-373. These microRNAs are the first to be reported for human retinoblastoma and may play significant roles in regulating tumorigenesis in the future.


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