New discoveries demonstrate important advantages of whole-genome sequencing in investigations of DNA ‘dark matter’ and shed light on the possible origins of cancer
Whole-genome scanning of cancer cells revealed significant mutations in the “dark matter” areas of melanoma DNA. This represents a leap forward in the basic science of cancer. Easier access to whole-genome sequencing means that researchers are poised to mine a rich vein of data that will shine a light on how cells malfunction.
For pathologists and clinical laboratory managers, these new research findings hold the promise to open up another approach to using the data in whole human genomes for diagnostic and therapeutic purposes. It also shows one more practical outcome from the rapidly falling cost of sequencing DNA.
Developing Medical Laboratory Tests That Analyze Dark Matter DNA
In two separate studies, researchers found mutations in the dark matter area of melanoma DNA, according to a story published by The New York Times. These mutations resulted in increased activity of the telomerase reverse transcriptase (TERT) gene. If this increased activity leads to increased expression of the gene, the result would be endless cell division. That means that these mutations might be among the first DNA changes in a cell’s path to melanoma.
“I am excited by the finding that regulatory mutations can apparently act as drivers of carcinogenesis,” stated cancer geneticist Elaine Mardis, Ph.D., in a story published in The Scientist. “This is great news for labs like ours that have always emphasized the importance of whole genome sequencing over exome or targeted sequencing.”
Mardis is Co-Director of the Genome Institute at Washington University in St. Louis, Missouri. She was not involved in the research.
It is significant that the discovered mutations are in regions that control genes, and not in the genes themselves. Until recently sequencing efforts focused almost exclusively on the protein-encoding regions of cancer genomes for two reasons.
First, there was the high cost of whole-genome sequencing. Second, it is easier to identify effects of mutations in protein-coding genes. Consequently, researchers have identified many recurrent mutations in protein-coding regions that contribute to cancer development, The Scientist reported. By contrast, they have identified very few such mutations in non-coding regions.
Glance into Melanoma Dark Matter May Reveal Origins of Cancer
The two studies used data from whole-genome scanning to identify mutations in the melanoma DNA dark matter. The journal Science published the papers in its February 22, 2013, issue.
“Sequencing the whole genome certainly adds a richness of discovery that can’t be fully captured with a whole exome,” observed Levi A. Garraway M.D., Ph.D., in a story published on the Broad Institute website. Garraway is an Assistant Professor at the Dana-Farber Cancer Institute at Brigham and Women’s Hospital. Garraway’s laboratory is part of the Broad Institute of Harvard University and Massachusetts Institute of Technology.
Next, they looked at patients with a far more common, non-inherited form of melanoma. The pair examined tissue samples from cancers at all stages. They found that 70% of specimens showed alterations in the telomerase gene switch.
In a contemporaneous study, Harvard Medical School researchers combed through data from whole-genome studies of melanoma cells. Franklin Huang, M.D., Ph.D., and M.D. Ph.D. student Eran Hodis found that 89% of the samples studied (17 out of 19) showed two mutations.
Huang and Hodis then sequenced an additional 51 samples. In total, they found the mutations in 71% of the samples (50 out of 70), according to the abstract published on the National Institutes of Health website. This mirrored the findings from the first study.
More Creative Approaches to Cancer Treatment
In both studies, the mutations were all found in the regulatory dark matter region of the TERT gene. The TERT gene encodes a component of telomerase. This enzyme is known to help protect the telomeres at the end of chromosomes to promote cell longevity. Overactivity of telomerase has been implicated in cancer growth.
In fact, abundant telomerase occurs in 90% of cancer cells, according to Harvard Medical School researcher Immaculata De Vivo, Ph.D., in the Times story. “We all knew telomerase was important for cancer, but now we are finding the mechanisms, the machinery,” she observed. De Vivo was not involved with the research.
“Altogether, this discovery could cause us to think more creatively about the possible benefits of targeting TERT in cancer treatment or prevention,” declared Garraway, senior author of the Harvard paper.
What is different in this research is that investigations focused on the dark matter DNA sequences between known human genes—not the genes themselves. Forward-looking pathologists and clinical laboratory managers may want to follow this research and look for the right time to create laboratory-developed tests that incorporate this knowledge in such a way that it helps physicians better diagnose cancer and make more effective treatment decisions.