A UCD group is trying to find why men now suffer from more aggressive forms of the disease, writes Dr Claire O'Connell
The recent heatwave has seen us welcome the sun with bare limbs, heads and even torsos. But exposing unprotected skin to those UV rays can have deadly consequences, and last month the National Cancer Registry predicted that by 2020 melanoma skin cancers will increase here by 130 per cent in women and 170 per cent in men.
Now researchers at University College Dublin (UCD) are looking at how genes are switched on or off as melanomas turn nasty. Their findings could help improve treatment and may eventually shed light on why men tend to get aggressive forms of the disease.
The team at UCD's Conway Institute works with cells in the lab that represent stages of melanoma as the disease develops from a benign to an aggressive form. Using gene-chip technology they rapidly screened the status of 7,000 genes in the different cell types.
They burst open the cells and took out the RNA, or working copies of the genes that were currently switched on. Then they washed the RNA over a centimetre-squared chip with around half a million probes on its surface, explains lead researcher Prof William Gallagher.
"The probes on the chip are short pieces of DNA sticking up," he says. "They are like fish-hooks so you can pull down particular genes."
The team compared the melanoma models and found 66 genes whose activation differed between the non-invasive and the aggressive disease - in the more dangerous form 22 were turned on and 44 were turned off. The list included genes with functions in pigmentation and in the immune system.
But the most dramatic result came from a gene called TSPY on the Y-chromosome, which is found only in men. "TSPY was the gene at the top of our list of genes that were turned off," says Prof Gallagher. "We went from the non-aggressive to the aggressive cells and we saw a really dramatic shut-off of expression."
The researchers, who published their findings in the journal Carcinogenesis, believe TSPY and a number of other genes on the list are switched off through a process called methylation. Normally when a gene is turned on, the relevant stretch of DNA uncoils briefly to allow its blueprint sequence to be copied into RNA. But in methylation, chemicals called methyl groups stick to the DNA and act like rocks on the tracks, blocking the cellular machinery from accessing and reading the gene's information. In cancer, methylation may switch off genes that normally protect the cell, explains Prof Gallagher.
"The classical way that a gene is knocked out in cancer is that it is deleted or there is a mutation, whereas in this case it appears the gene is still present and in a specific methylation event the gene is turned off," he says.
"We are suggesting there is a group of genes that are turned off globally collectively by this mechanism and this could be a fundamental mechanism in melanoma progression."
They have already shown that the anti-methylation chemotherapy agent DAC switches TSPY back on in the aggressive melanoma cells and slows tumour growth. But Prof Gallagher says it is too early yet to determine whether TSPY is normally protective or that its location on the Y-chromosome could explain why men tend to get more aggressive melanomas than women.
"There is not too much known about the function of TSPY, it is a very complicated gene," he says.
More immediately, the UCD team is working with staff at the Mater Hospital to see if TSPY and other genes on the list could act as useful markers for prognosis or treatment. They are currently developing a novel, automated system to screen hundreds of tumour samples for proteins encoded by the genes. They hope their work, which is funded by the Health Research Board and Cancer Research Ireland, will ultimately yield useful clinical markers for determining the severity of melanoma and monitoring therapy.
Prof Gallagher has organised an international symposium on recent advances in melanoma research to take place at the Conway Institute next Monday.