Science in Mind

Boston researchers discover mutations that underlie melanoma in ‘junk DNA’

Again and again, recent studies of cancer genetics have revealed that what once appeared to be a single disease—such as breast or lung cancer—is really a mosaic made up of many different subtypes, each with its own genetic roots that may require its own targeted therapy.

Now scientists working independently in Boston and Germany have made a surprising discovery: a set of genetic mutations found in most melanomas, the deadliest skin cancer. The presence of these mutations in the vast majority of tumors studied suggests that the researchers may have stumbled upon a fundamental mechanism involved in a hallmark trait of cancer cells—their ability to live forever—that could one day be targeted by drugs.

Outside researchers said the work, published online Thursday in the journal Science Express, is exciting because the conclusion is the opposite of what many exhaustive studies of cancers have shown.

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“One of the striking features is how remarkably common the mutation is,” said Dr. David Fisher, director of the melanoma program at Massachusetts General Hospital, who was not involved in the research. “What’s so important about this observation is it sharpens the focus on this mechanism—this is kind of a smoking gun.”

Melanoma is responsible for 9,000 deaths a year in the United States.

Both teams were surprised by their convergent results, which also suggest that the area of the genome where the mutations were found—one that has been neglected, largely because of the cost and difficulty of studying it—should be scoured to look for the genetic underpinnings of other cancers.

There has been growing attention to the importance of this part of the genome, which is sometimes called “junk DNA” because it lies between the genes that contain the instructions for making proteins. Researchers have long known that is a misnomer; the area plays an important role in regulating gene activity. But the cost of generating the data and complexity of the analysis have been barriers. Most mutations—and all of the commonly occurring cancer mutations discovered thus far—had been in what Dr. Levi Garraway calls the “business end” of the genome, the segments of DNA that make up genes.

Garraway, an associate professor of medicine at Dana-Farber Cancer Institute and the Broad Institute, a genomics research center in Cambridge, led a team that examined the complete DNA blueprint of dozens of melanoma tumors, on the off chance they might find an important mutation in the area without genes. Meanwhile, a group of researchers in Germany sequenced the genomes of a family in which 14 people had succumbed to a rare form of inherited melanoma.

Both teams zeroed in on mutations in a part of the genome called a promoter, which acts like a volume knob on a stereo to control gene activity. The gene that the promoter controlled happened to be one that has long been of interest in cancer because it creates part of an enzyme called telomerase, which enables cancer cells to continue to divide indefinitely as one of its key jobs. Still, it wasn’t easy for the researchers to convince themselves that what they found, underlying more than two-thirds of melanoma cases, was real.

“We didn’t believe it at first; we thought there must be an artifact, something wrong,” Garraway said, adding that publication was delayed for almost a year while the scientists checked their results.

“If it’s not real, it would make us look silly. And if it’s real, it deserves a real assessment,” Garraway said, recalling the discussion in the laboratory.

Using old-fashioned sequencing methods to carefully verify their initial finding, the researchers eventually found two mutations existed in 71 percent of the 70 melanoma samples they analyzed. The mutations were also found more broadly, in small numbers of bladder and liver cancers.

Meanwhile, German researchers were studying a family with a rare type of inherited melanoma, in the hopes that if they could pinpoint the gene involved, it would provide clues about the more common versions of the disease. Like the Boston team, to their surprise, they did not find a mutation in a gene—but in a portion of a promoter. Only after they had submitted their paper did they learn that the Boston group, using very different techniques, had arrived at the same conclusion.

“Definitely, it was a big relief,” said Rajiv Kumar, a professor of molecular genetic epidemiology at the German Cancer Research Center and one of the leaders of the work.

Next, the researchers plan to understand more completely the function of the mutations, to see whether they drive a cancer or are essential for a tumor to maintain itself. The research could spur the search for drugs that target the mechanism. And, it will likely prompt researchers to do similar studies of other tumor types as the cost of producing full DNA blueprints of tumors continues to drop and more of that data becomes available.

Dr. Paul Chapman, an attending physician at Memorial Sloan-Kettering Cancer Center who was not involved in the research said that he is not sure whether a drug that blocked this mechanism alone would be enough to knock out cancer, since the cancer cells could probably still live long enough to kill patients.

But he said the research is an important contribution and an unexpected result that will likely intensify cancer researchers’ focus on the vast areas of the genome that contain no genes.

“When you look at the mutations in a whole genome, something like 80 to 90 percent occur in non-[protein] coding regions, and those are not all just junk mutations,” Chapman said. “People are becoming more and more interested in that, and here’s a great example.”

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