A team led by researchers at the National Institutes of Health (NIH) is the first to systematically survey the landscape of the melanoma genome, the DNA code of the deadliest form of skin cancer. The researchers have made surprising new discoveries using whole-exome sequencing, an approach that decodes the 1–2% of the genome that contains protein-coding genes. The study appears in the April 2011, early online issue of Nature Genetics.

Melanoma is the most serious form of skin cancer and its incidence is increasing faster than any other cancer. A major cause is thought to be overexposure to the sun, particularly ultraviolet radiation, which can damage DNA and lead to cancer‑causing genetic changes within skin cells.

The researchers conducted a comprehensive genome analysis and explored the melanoma genome’s functional components, especially gene alterations, or mutations. They studied advanced disease — the metastatic stage — when cells have the highest accumulation of gene mutations.

‘Melanoma is one of the most challenging solid cancers to work with because it has such a high rate of mutation,’ said senior author Yardena Samuels, investigator in the Cancer Genetics Branch of the NHGRI’s Division of Intramural Research. ‘Whole-exome sequencing will help us identify the most important changes.’

NHGRI researchers and a colleague from the Johns Hopkins Kimmel Cancer Center in Baltimore designed and analysed the new study, while National Cancer Institute (NCI) researchers and colleagues from the University of Texas MD Anderson Cancer Center in Houston, and the University of Colorado Denver School of Medicine collected melanoma tumour samples.

As a first step in the study, NHGRI researchers obtained 14 metastatic melanoma tumour samples and matching blood samples from a collection maintained at NCI. Whole-exome sequencing of the 28 samples was performed at the NIH Intramural Sequencing Center.

The exome sequence data required a number of analytic steps to separate functionally important mutations from a large number of total results. The first of these analyses differentiated the mutations that occur sporadically in the tumour, called somatic mutations, from inherited mutations. It entailed a comparison between the mutations observed in the blood samples and those from the tumour cells of the same individual. Researchers eliminated from further analysis any tumour mutations that also occurred in normal tissue.