Findings published in Nature Genetics by researchers at Sahlgrenska Academy describe their detailed mapping of the way that the TERT gene is activated in tumors. Given that activation of the gene is necessary if the telomeres of cancer cells are not to become shorter while dividing, it is a key to cell division in tumor growth.
The four authors—Johan Fredriksson, Jonas Nilsson, Lars Ny and Erik Larsson Lekholm—are all affiliated with Sahlgrenska Academy.
Researchers discovered long ago that mutations in protein-coding genes are vital to tumor formation. But protein-coding sequences account for only 3% of human chromosomes and very little is known about the role played by mutations in other regions during the development of cancer. Researchers discovered recently that somatic (nonhereditary) mutations in a noncoding regulatory region can activate the TERT gene in tumors. Cell division normally involves gradual shortening of the telomeres, which are caps at the end of chromosomes. The process, which normally limits cell division, is inhibited once TERT has been activated. The new findings published in Nature Genetics offer a detailed mapping of the way that TERT is activated by means of regulatory mutations in various forms of cancer.
“One unexpected result was that TERT mutations also appear to activate CLPTM1L, a nearby gene that has previously been shown to make tumor cells more resistant to chemotherapy,” says Dr. Fredriksson, a postdoc who is the principal author of the article. “In other words, these mutations may have more of a multipronged impact on tumor growth than previously believed.”
The article also describes a new bioinformatic method for systematically identifying associations between somatic mutations and changes to gene activity (transcription). TERT mutations turned out to be exceptional in terms of both potency and frequency.
Dr. Larsson Lekholm, who coordinated the study, says that the project provides a powerful springboard for identifying functional somatic mutations in noncoding regions. “While our hypothesis is that other important associations remain to be discovered, larger patient populations and refined methods will probably be needed before we can establish them with statistical certainty. A number of noncoding regions also exhibit interesting mutation patterns that seem to be non-random even though there is no apparent link to gene expression. Our focus at this point is on follow-up studies in order to better understand these mechanisms.”
Read the article: http://www.nature.com/ng/journal/v46/n12/full/ng.3141.html
