Significant step forward in childhood eye cancer
Researchers at a children's hospital in Washington have identified the genetic mechanism behind the rapid development of retinoblastoma, a rare type of childhood eye cancer.
Their findings also point to a potential new way to treat the cancer, according to work published in the journal Nature.
Retinoblastoma develops in the retina - the light-sensing tissue at the back of the eye. It affects more than 5,000 children worldwide every year, many of them under the age of five.
More than nine in 10 cases can be cured if the disease is detected early enough, but the prognosis can be worse for children whose cancer is identified after it has spread beyond the eye - as is often the case in developing countries.
It has long been known that virtually all retinoblastomas are caused by damage to a gene called RB1.
However, until now scientists haven't been able to identify the subsequent steps involved in the disease's development, which can be extremely rapid.
To try to understand this, experts from the Paediatric Cancer Genome Project at St Jude Childrens Research Hospital sequenced the entire genomes of four children with retinoblastoma, to look for other damaged genes.
Surprisingly, they found very little sign of DNA damage. In fact, the retinoblastoma tumours sequenced contained about 15-fold fewer mutations than have been found in nearly all other cancers sequenced so far.
They then ran other tests looking at so-called 'epigenetic' modifications - chemical alterations to DNA that switch genes on or off.
They found that retinoblastoma cells were substantially different from their normal counterparts, in that a whole range of genes were regulated differently by this mechanism, but without any obvious DNA damage.
Researcher Dr Michael Dyer said: "The dogma in the field has been that once RB1 is mutated, the genome of the affected cell becomes unstable, chromosomes begin to break and recombine, and mutations quickly develop in the pathways that are essential for cancer progression.
"What we found through the Paediatric Cancer Genome Project was exactly the opposite. These tumours contain very few mutations or chromosomal rearrangements."
He added: "To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells."
The researchers also identified the SYK gene as a potential new treatment target.
When they used experimental drugs to block SYK in human retinoblastoma cells growing in the laboratory or in the eye of a mouse, the cells died.
Work is now underway to reformulate one of the experimental drugs, a SYK-inhibitor called R406, so it can be delivered directly into the eye. If successful, those efforts are expected to lead to a Phase I trial in retinoblastoma patients.
Dr Laura Bell, senior science information officer at Cancer Research UK, said the "fascinating" discovery challenged the conventional view of how retinoblastoma develops. "Even more importantly," she added, "it suggests a novel way to treat the disease".
"But further work is needed to see if this mechanism drives the development of all retinoblastomas. If confirmed, then this work could be the first step towards a new treatment that could improve survival for children with this rare type of cancer, and could help to preserve vision in children who would otherwise undergo radiotherapy or surgery."
Copyright Press Association 2012