Landmark Research Links Melanoma to UV Radiation

In December 2009, a remarkable new study made perhaps the strongest case ever that some melanomas are caused by exposure to ultraviolet (UV) radiation.

Scientists at The Wellcome Trust Sanger Institute, in Hinxton, UK, mapped the complete genetic material (the genome) that composed a melanoma taken from a patient with the disease. Using new molecular technology, the researchers identified thousands of mutations, the vast majority of which were caused by UV radiation. Many mutations, changes or errors that occur in genes due to radiation, viruses, and other causes, can ultimately lead to cancer.

"The melanoma genome contains more than 33,000 mutations, many of which bear the imprint of the most common cause of melanoma - exposure to ultraviolet light."

Over the years, evidence has added up that most skin cancers are caused by damage to the skin cells' DNA by the sun's UV radiation, but this was the first time UV damage could be seen all through a melanoma's genetic material. According to the Sanger Institute, "The melanoma genome contains more than 33,000 mutations, many of which bear the imprint of the most common cause of melanoma - exposure to ultraviolet light."

In the study, the genomes of both normal and melanoma tissue were decoded. When the tissues were compared, scientists were able to pinpoint precisely where in the melanoma genome mutations occurred.

"With this genome sequence, we have been able to explore deep in the past of each tumor, uncovering with remarkable clarity the imprint of these environmental mutagens [causes of the mutations] on DNA, which occurred years before the tumor became apparent," the study's coauthor, Professor Mike Stratton, MD, PhD, explained. "We can see the desperate attempts of our genome to defend itself against the damage from ultraviolet radiation. Our cells fight back furiously to repair the damage, but frequently lose that fight."

It's not clear to just what extent UV radiation influences the development of melanoma, but this research strengthens the link between them. While 90 percent of all basal and squamous cell carcinomas (the two most common skin cancers) are known to be associated with exposure to UV radiation (UVR), some investigators have disagreed about the role of UVR in melanoma development. Research has established that genetics are an important component in melanoma (a family history of the disease increases one's risk of developing it), and some scientists have maintained there was no convincing proof of UVR's involvement. But this new cataloging of mutations, the results of which were published in Nature, all but confirms UV radiation as a cause of melanoma.

The link between melanoma and UV radiation is further reinforced by information gleaned from a companion study of a patient's lung cancer genome, also recently mapped by scientists at the Wellcome Trust Sanger Institute. The pattern of mutations in both cancer genomes is extremely similar; just as the vast majority of mutations in the melanoma genome were caused by UV damage, a significant majority of the mutations in the lung cancer genome were caused by cigarette smoking. "The profile of mutations we observed [in the lung cancer genome] is exactly that expected from tobacco, suggesting that the majority of the 23,000 we found were caused by the cocktail of chemicals found in cigarettes," according to Dr. Peter Campbell, senior author of the lung cancer study. Most lung cancer deaths are known to be caused by smoking, and it could well be that most melanoma deaths are caused by UV.

"These are the two main cancers in the developed world for which we know the primary exposure," Dr. Stratton said. "For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight."

Not all mutations cause cancer, so the scientists will next try to determine exactly which mutations contribute to melanoma development. "The knowledge we extract over the next few years will have major implications for treatment," said Dr. Campbell. "By identifying all the cancer genes, we will be able to develop new drugs that target specific mutated genes, and work out which patients will benefit from these novel treatments."

Published on April 16, 2010