In a leap forward in understanding the basic science of one of the most lethal cancers, two groups of researchers have found mutations in most melanomas that are unlike any they have seen before in cancer.
The changes are in regions that control genes, not in the genes themselves. The mutations are exactly the type caused by exposure to ultraviolet light, indicating they might be among the first DNA changes in a cell’s path to melanoma.
The discoveries, published online Thursday in two papers in the journal Science Express, do not suggest new treatments or ways to prevent melanoma, researchers said. But the findings help explain how melanomas — and, possibly, other cancers — develop and grow, insights that may lead to develop ways to prevent or stop the cancer.
For years, cancer researchers have searched for mutations in genes, but this time, they looked for — and found — mutations in a region that regulates genes. They did it by examining the entire DNA of multiple tumors, studying not just genes but also what has been called the dark matter, the 99 percent of the DNA that includes regions that control genes.
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“You could think of this as one glimmer in what has been called cancer’s dark matter,” said Dr. Levi Garraway, of the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT.
The complete DNA sequences of 70 malignant melanomas led to the discovery by Garraway’s team. A small control region was mutated in seven of 10 of the tumors, and, the investigators found, in liver and bladder cancers. The cancer cells had one of two tiny changes that together were more common than any mutation ever found in the genes of melanoma.
In the second study, a team led by Rajiv Kumar of the German Cancer Research Center in Heidelberg, and Dirk Schadendorf of the University of Essen, looked for the mutations in a family whose members tended to get melanoma.
Four relatives who developed melanoma had inherited one of the mutations, while four who remained melanoma-free didn’t. They also found the mutation in a 36-year-old member of the family who had not developed melanoma but had had many moles, often a sign of risk in families prone to melanoma.
Their findings indicate that those who inherit the mutations might be born with cells that have taken a first step toward cancer.
The mutations spur cells to make an enzyme, telomerase, that keeps cells immortal by preventing them from gradually losing the ends of their chromosome, the telomeres. When telomeres erode, a cell dies. But the enzyme also has other, poorly understood functions that are thought to keep cancer cells alive, said Robert Weinberg, an MIT researcher who was not involved with the research.
“The paradigm that it does nothing but extend telomeres is a gross oversimplification,” he said.
Abundant telomerase is so important to cancers that it occurs in 90 percent of them, said Immaculata De Vivo, a Harvard Medical School researcher who also was not involved with the research.
The results of the two studies presented in the papers “are like a court of law — it’s the preponderance of the evidence,” she said. “We all knew telomerase was important for cancer, but now we are finding the mechanisms, the machinery.”
Scientists were surprised that the mutations in the dark matter of melanoma tumors were so commonplace. Garraway and his colleagues had the entire DNA sequences for a collection of melanomas — genes as well as the rest of the DNA including areas that turn genes on and off.
“We said, ‘Let’s just take a look and see if there are any mutations in a regulatory region,’ ” Garraway said.
At first, they looked at the DNA sequences of 19 tumors. They were amazed to find one or the other of the two mutations in 17 of them. So the researchers looked at 51 more melanomas and a handful of bladder and liver cancers. The mutations popped up again.
It’s not clear how to reverse the mutations’ cancer-causing effects, Garraway said. And although people have long wanted to block telomerase production in cancer cells, they have not found a drug to do it.