Genetic Study Yields New Clues to Melanoma
April 19, 2011 • Volume 8 / Number 8|
In the largest genetic survey of melanoma tumors to date, researchers have sequenced the genes of 14 untreated patients with advanced disease. The results, published online in Nature Genetics on April 15, point to additional genes and pathways not previously associated with melanoma that may play a role in the disease.
Dr. Yardena Samuels of the National Human Genome Research Institute and her colleagues sequenced the protein-coding genes (also called the exome) of tumor cells and of matched normal cells from the same individuals. The tissue samples came from patients subsequently treated by study co-author Dr. Steven Rosenberg, chief of the Surgery Branch in NCI’s Center for Cancer Research.
The sequencing revealed alterations in 16 genes that may contribute to the disease. Among these, only the BRAF gene had been linked to melanoma previously. In an unexpected finding, the researchers discovered the same mutation in a gene called TRRAP in six different individuals with melanoma. TRRAP encodes a protein that helps control cell proliferation. The recurrent nature of the mutation at the same amino acid location suggests that it plays a role in the disease, the researchers noted.
Recurrent mutations were also found in a gene called GRIN2A. (The protein product of GRIN2A is a subunit of a type of glutamate receptor.) In a larger analysis of 135 melanoma tumors, the gene was mutated in 25 percent of the samples, making it one of the most highly mutated genes in melanoma identified so far. An analysis of signaling pathways confirmed that the glutamate pathway may play a role in melanoma, as had been reported previously in Nature Genetics.
“This is the most comprehensive view of the melanoma genetic landscape to date,” said Dr. Samuels, noting that many more genomes need to be sequenced to understand the genetic picture of the disease completely. The work builds on an earlier study by the same group that involved sequencing families of genes. A single whole-genome sequence of a patient with melanoma was first reported last year by researchers at the Wellcome Trust Sanger Institute.
“We can derive genetic data from tumors efficiently, and we can do the analysis,” Dr. Samuels said. “But the main challenge will be to find out which of the mutations are important in the disease and apply the findings to patient care.”
NCI Cancer Bulletin for April 19, 2011 - National Cancer Institute
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