Two recent studies have identified genes that may contribute to the development of melanoma and make melanoma cells resistant to treatment.
Researchers at the Dana-Farber Cancer Institute have discovered two mutations in gene regulatory regions that together occur in 71% of malignant melanoma tumors. In an article published in Science, the investigators say that these highly recurrent mutations may be the most common found to date in melanoma cells. Both are somatic telomerase reverse transcriptase (TERT) gene promoter mutations.1
Many cancer-associated mutations have been identified in the protein-coding regions of genes, but these may be the first to be found in regions that regulate the expression of genes, which make up 99% of the cellular genome.
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“This new finding represents an initial foray into the ‘dark matter’ of the cancer genome,” said Levi Garraway, MD, PhD, the senior author of the article. “In addition, 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 cause us 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. Telomerase reverse transcriptase is an enzyme that prevents cell death and is often overexpressed in cancer cells.
“We think these mutations in the promoter region are potentially one way the TERT gene can be activated,” said Franklin Huang, MD, PhD, another of the article’s authors.
The researchers investigated the effect of the mutation by using a reporter assay to clone the mutant TERT promoter in a gene that codes for luciferase, a light-emitting protein, in a laboratory cell line. Observing that the mutant TERT promoter increased the production of luciferase, the investigators concluded that, in human pigmented skin cells, it accelerates the activity of the TERT gene, thereby contributing to the development of melanoma.1
These mutations were discovered when the researchers examined data from whole-genome sequencing of malignant melanoma tumors. Unlike whole-exome searches, which examine only the protein-coding portions of the cell genome, a whole genome search scans all DNA, including the “dark matter.” The investigators examined cells from 70 melanomas and identified the TERT mutations in 50 of them.
The same mutations are present in cell lines from other malignancies and may be especially common in bladder and liver cancers, according to the study authors.
Gene Linked to Poor Prognosis in Melanoma
Researchers at the University of London have found that the presence of the gene TP63, which codes for the protein p63, is associated with a higher risk of death in patients with melanoma.2 The protein, which was found in more than half of the 156 melanoma samples the investigators analyzed, interferes with apoptotic pathways and makes tumor cells more resistant to treatment. Although p63 was not expressed in primary melanocytes, it was observed in melanoma cell lines and clinical samples. Since TP63 promotes chemoresistance, the authors suggest that it may one day be a therapeutic target in patients with melanoma.
References
1) Huang FW, Hodis E, Xu MJ, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013 Feb 22;339(6122):957-9. doi: 10.1126/science.1229259. Epub 2013 Jan 24.
2) Matin RN, Chikh A, Law Pak Chong S, et al. p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis. J Exp Med. 2013 Mar 11;210(3):581-603. doi: 10.1084/jem.20121439. Epub 2013 Feb 18.
