Noncoding, But Important Mutations Found in Vast Majority of Melanomas

It is always gratifying to see two research groups ask similar questions, use different approaches, and converge on the same answer. Researchers on both sides of the pond—at the Dana Farber Cancer Institute and the Broad Institute of Harvard and MIT in Cambridge, Massachusetts, as well as at the German Cancer Research Center and the University Hospital Essen in Germany—found that mutations in a noncoding DNA segment in the TERT gene are highly prevalent in melanoma tumors. Each group only found out about the other’s results after submitting its own research for publication.

These newly discovered TERT mutations occur in more than 70% of malignant melanomas. They are even more abundant than mutations in the BRAF gene, which are found in approximately 40% to 50% of malignant melanomas. The TERT gene codes for an enzyme called telomerase, which helps protect chromosome ends (telomeres) from gradually eroding. When a cell loses all of its telomeres, it dies. Telomerase adds extra DNA to the ends to keep cells alive.

The Harvard group found two mutations in the noncoding DNA portion of TERT in 70% of the melanoma tumors examined. This noncoding region of the gene is called the promoter and helps regulate the activity of the gene. The researchers, including Franklin Huang and Levi Garraway, found the mutations by sequencing both the protein-coding and noncoding regions of 70 melanoma tumors; a technique called whole genome sequencing. Both mutations activate the TERT gene and cause an increase in telomerase production. The researchers believe that this increased telomerase activity contributes to the development of melanoma.

The Harvard researchers also examined 150 cancer cell lines derived from various tumor types and found the TERT mutations in 16% of the cell lines (24 cases). Bladder and liver cancer cell lines also appear to have a higher frequency of these mutations.

The German group—led by Susanne Horn and Rajiv Kumar of the German Cancer Research Center and Dirk Schadendorf at the University of Essen—found similar mutations while looking for novel mutations linked to melanoma in families whose members are more frequently diagnosed with the cancer. Like the Harvard team, the researchers used whole genome sequencing. They found a germ line (heritable) mutation in the promoter of the TERT gene that increases the amount of telomerase made by cells.

According to Kumar and Schadendorf, approximately 10% of melanoma cases are a result of familial or inherited melanoma, but prior to this study, only two genes, CDKN2A and CDK4, had been shown to have germ line mutations linked to melanoma. These two mutations account for 40% of familial melanomas. Now, TERT can be added to the list.

The German team confirmed the findings of the Harvard group by finding similar TERT promoter mutations in tumors from noninherited cases of melanoma. These mutations also increased the activity of telomerase. Interestingly, the mutations appeared to be of a type frequently caused by ultraviolet (UV) radiation exposure.

These novel TERT abnormalities are the first mutations associated with cancer that have been found in regions of the DNA that do not code for a protein.

“These findings suggest that there may be other important mutations occurring in noncoding regions of the genome that could be identified using whole genome sequencing approaches,” say Huang and Garraway.

Both groups believe that these new mutations are driver mutations—that is, mutations that promote tumor formation and progression. Driver mutations are often potential drug targets, since they are usually necessary for the development of advanced-stage cancer. Several cancer therapies that target telomerase are in development. The Harvard group is now trying to understand whether these newly found mutations could help identify other types of cancer that could be treated with the new telomerase inhibitors in combination with established therapies.

Both groups are also examining more tumor samples to investigate the relationship between these mutations and other disease features, including response to therapies. The German group also wants to figure out whether the mutations are present at the onset of melanoma or are only acquired in later stages of the disease.

“We hope these findings will contribute to our understanding of the development of melanoma,” Huang says. “Ultimately, we hope that these findings, in conjunction with the findings of our colleagues reporting similar results, will lead to improvements in the care of patients with melanoma and other cancers.”

Both studies were published in the same issue of Science:

Huang FW, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013. doi: 10.1126/science.1229259

Horn S, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013. doi: 10.1126/science.1230062