Malignant melanoma – the most dangerous form of skin cancer – is a cunning adversary. Once it has started spreading through the body, the disease is difficult to treat effectively. The cancer cells seem to shrug off the effects of DNA-damaging chemotherapy drugs, repairing themselves, and continuing to multiply as before.
As a result, many melanomas remain stubbornly resistant to chemotherapy. Fewer than one in five patients receiving chemo show any response to the treatment, and it is currently impossible to tell who might benefit from the drugs.
A new report from Cancer Research UK scientists at the University of Leeds now reveals the secret behind melanoma’s self-healing powers. Led by Professor Julia Newton-Bishop, the team found that overactive DNA repair genes are responsible for the cancer’s resistance to chemotherapy.
It’s an odd discovery because these genes usually protect us against cancer, but here, they’re helping cancer cells to beat our toughest drugs. This knowledge could help doctors to treat melanoma patients more effectively in the future.
Small tumours – big problem
Many studies of gene activity in cancer cells rely on analysis of RNA (the chemical ‘messenger’ produced when genes are active) extracted from frozen tumour samples. This is because freezing doesn’t do too much damage to the delicate RNA strands. But the relatively small size of melanomas on the skin makes this technique quite tricky, as it’s difficult to get enough tumour for freezing and testing.
To overcome this challenge, Professor Newton-Bishop and her team have developed a way to test RNA in melanomas preserved in a chemical called formalin – a technique commonly used in hospitals to preserve tumour samples for analysis under the microscope.
The researchers gathered formalin-preserved melanoma samples from nearly 500 patients, mostly diagnosed between 2000 and 2006, and extracted RNA from them. Then they tested the RNA against a panel of more than 500 genes, to see which ones were more or less active compared to samples from healthy skin cells.
Because the researchers also had access to medical information about how the patients’ cancers had progressed, they could cross-check to see whether certain genes were more active in tumours that did or didn’t respond to chemotherapy.
An unexpected role for repair
When the scientists looked at the results from tumours that had failed to respond to chemotherapy, or that had come back after treatment, they found one particular group of genes that was particularly active – DNA repair genes.
This is somewhat unusual, because most cancers have underactive or broken DNA repair pathways. For example, faults in the DNA repair genes BRCA1 or BRCA2 can greatly increase a woman’s risk of breast cancer. If cells can’t repair their DNA, they accumulate the very damage that eventually turns them cancerous. So DNA repair genes usually protect against cancer but that’s clearly not the case here.
Professor Newton-Bishop and her team suspect that the over-active DNA repair genes in melanoma cells are helping to counteract the DNA-damaging effects of chemotherapy. Although it’s not currently clear exactly why these genes go into overdrive, they could provide useful pointers to help doctors decide the best way to treat patients.
Assessing the benefits
As we mentioned earlier, more than four out of five melanoma patients don’t respond to chemotherapy, presumably because their tumours contain overactive DNA repair genes. So testing patients’ tumours for levels of repair gene activity would be a useful way to identify the one in five who would benefit the most from chemotherapy, thereby avoiding giving toxic drugs – with potentially unpleasant side effects – to those who are unlikely to be helped by them.
At the moment, we’re still some way away from having a test that doctors can use to help treat people with melanoma more effectively, as there’s still a lot more lab work and testing to be done. But this is step towards that goal, and highlights an important area for future research.
- Most melanomas are caused by overexposure to ultraviolet radiation from the sun and sunbeds. Find out how you can reduce your risk of the disease on our SunSmart website.
Jewell, R. et al (2010). Patterns of Expression of DNA Repair Genes and Relapse from Melanoma Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-10-1521