Researchers discover new mutations driving melanoma
Discovery of mutations in DNA previously not linked to cancer-causing alterations highlights the value of whole-genome searches of tumour DNA
- Date : 29 Jan 2013
- Topic : Melanoma
Two new mutations that collectively occur in 71% of melanomas have been discovered in what scientists call the "dark matter" of the cancer genome, where cancer-related mutations haven't been previously found. These highly recurrent mutations may be the most common mutations in melanoma cells found to date.
Reporting their findings in the January 24 issue of Science Express, the researchers from Dana-Farber Cancer Institute and the Broad Institute said these cancer-associated mutations are the first to be discovered in the vast regions of DNA in cancer cells that do not contain genetic instructions for making proteins. The mutations are located in non-protein-coding DNA that regulates the activity of genes. This non-coding DNA accounts for 99% of a cell's genome. A large number of oncogenic mutations in cancer have been identified in the past several decades, but all have been found within the actual genetic blueprints for proteins.
According to Dr Levi Garraway of Dana-Farber and the Broad Institute and the article's senior author, this represents the discovery of two of the most prevalent melanoma gene mutations. Considered as a whole, these two TERT promoter mutations are even more common than BRAF mutations in melanoma. Altogether, this discovery could lead to think more creatively about the possible benefits of targeting TERT in cancer treatment or prevention.
The mutations affect a promoter region adjacent to the TERT gene. TERT contains the recipe for making telomerase reverse transcriptase, an enzyme that can make cells virtually immortal, and is often found overexpressed in cancer cells. A promoter region of DNA controls the rate of a gene's transcription.
The scientists consider these mutations in the promoter region as potentially one way the TERT gene can be activated, according to Dr Franklin Huang, co-first author of the report along with Harvard MD, PhD student Eran Hodis, of Dana-Farber and the Broad Institute.
To investigate the mutation's effect, the researchers hooked the mutant TERT promoter to a gene that makes luciferase – a light-emitting protein. They observed that the mutant promoter increased the production of luciferase in laboratory cell lines. In the same way, the scientists presume, the mutant promoter in human pigmented skin cells can send the TERT gene into overdrive, potentially contributing to the development of melanoma.
The mutations were discovered when the scientists sifted through data from whole-genome sequencing of malignant melanoma tumours. Unlike whole-exome searches that examine only the protein-coding DNA of a cell's genome, whole-genome searches scan of the DNA, including the non-coding regions.
In analyzing whole-genome data, the investigators discovered the two somatic, or not-inherited, mutations in 17 of 19 (89%) of the tumours. Next, they sequenced a larger number of melanoma tumours and found that the two mutations were present in 71% of tumours in total.
The researchers said the same mutations are present in cell lines from some other malignancies, and that preliminary evidence showed they might be unusually common in bladder and liver cancers. They also noted that the discovery of these mutations in DNA previously not linked to cancer-causing alterations highlights the value of whole-genome searches of tumour DNA.
The research was supported in part by the USA National Institutes of Health (T32 CA009172, T32GM07753, DP2OD002750, and R33CA126674), the Mittelman Family Fellowship, the American Cancer Society, the Novartis Institutes for Biomedical Research, the Melanoma Research Alliance, and the Starr Cancer Consortium.
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