US scientists have found two new mutations in non-coding (formerly dubbed “junk”) DNA that occur in 71% of malignant melanomas. They say the highly recurrent mutations may be the most common in this deadliest form of skin cancer, more common than the already well-known protein-coding BRAF gene, and may well offer an alternative target for treatment.
Researchers from the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, report their discovery in the 24 January issue of the journal Science Express, which publishes selected Science papers online in advance of print.
Nearly 99% of the human genome comprises what was once labelled “junk DNA” because unlike the other 1% or so, it does not contain blueprints for making proteins, the building blocks of life. Now scientists are beginning to discover that sections of DNA in this “dark matter” of the genome are “non-coding” genes that control the behavior of protein-coding genes.
For example, last week, MIT biologists reporting a study in Cell, describe how a piece of non-coding DNA they dubbed “Braveheart” controls the transformation of stem cells into heart cells, and without which the embryonic process of building a heart never gets started.
The researchers in this latest study say theirs are the first cancer-related mutations to be found in non-coding DNA; until now all the cancer genes that have been discovered have been protein-coding ones.
Senior author Levi Garraway of Dana-Farber and the Broad says in a statement:
“This new finding represents an initial foray into the ‘dark matter’ of the cancer genome.”
He says not only are the mutations the first cancer-genes to be discovered in non-coding DNA, but they appear also to be the two most common cancer genes:
“Considered as a whole, these two TERT promoter mutations are even more common than BRAF mutations in melanoma,” he adds, explaining that:
“Altogether, this discovery could cause us to think more creatively about the possible benefits of targeting TERT in cancer treatment or prevention.”
The TERT promoter mutations are in a stretch of DNA that sits next to the gene that contains the blueprint for making an enzyme called telomerase reverse transcriptase (TERT), which increases cell life almost indefinitely. The TERT gene is often overexpressed in cancer cells, making them virtually immortal.
A promoter mutation controls the rate at which the DNA blueprint is translated into instructions inside cells for making the corresponding protein: in this case the rate at which the TERT enzyme is produced.
Co-first author Franklin Huang says:
“We think these mutations in the promoter region are potentially one way the TERT gene can be activated.”
He and his colleagues say the same mutations are to be found in cell lines from some other cancers: there is some early evidence they may be unusually common in cancers of the bladder and of the liver.
They note the discovery highlights the value of searching the whole genome, and not just the coding sections of DNA, to find potential new gene targets for cancer treatment.
Funds from the National Institutes of Health, the Mittelman Family Fellowship, the American Cancer Society, the Novartis Institutes for Biomedical Research, the Melanoma Research Alliance, and the Starr Cancer Consortium helped finance the study.
Written by Catharine Paddock PhD