New research heavily implicates a genetic phenomenon commonly known as “jumping genes” in the growth of tumors.
Since jumping genes aren’t mutations—mistakes in the letters of the DNA sequence— traditional cancer genome sequencing can’t identify them. As such, this study opens up new lines of research for future cancer therapies that might target such genes.
Jumping genes, which scientists call transposable elements, are short sections of the DNA sequence that the genome has incorporated randomly over the long course of human evolution. Much current research focuses on the evolutionary histories of jumping genes, but researchers think viral infection may play an important role in their origins.
‘On switches’
Researchers have plumbed genomic databases, looking specifically for tumors whose jumping genes are driving cancer growth. In the new study, researchers found that many cancers that switch into overdrive and boost tumor growth have jumping genes that function as a kind of stealthy “on switch.” These cryptic switches can force a gene to be “on” all the time, even though it should be off.
“If you perform typical genome sequencing looking for genetic mutations driving cancer, you’re not going to find jumping genes,” says Ting Wang, a professor of medicine at Washington University School of Medicine in St. Louis.
“Jumping genes are more important in some cancer types versus others, but on average, we found at least one of them activating a cancer gene in about half of all the tumors we studied. This is important information because these tumors also tended to be aggressive, so doctors might treat them more aggressively if they could know this in advance. It also provides new targets to study for future cancer therapies.”
Wang and his colleagues studied 7,769 tumors across 15 cancer types collected as part of The Cancer Genome Atlas project. The project is a national effort to characterize the genetic roots of cancer that the National Institutes of Health funds. The researchers found 129 jumping genes acting as stealthy on switches for 106 cancer genes in 3,864 tumors, including breast, prostate, lung, colon, skin, and brain cancers.
While jumping genes were present across cancers, their importance varied widely by tumor type. For example, at least one jumping gene was activated in 12 percent of gliomas, a type of brain cancer. In contrast, 87 percent of lung squamous cell carcinomas harbored jumping genes. They also found one activated jumping gene that was specific to melanoma.
New treatments?
The study opens up new avenues of research for cancer therapeutics based on an understanding of gene regulation rather than mutation, according to the researchers. They found that jumping genes serving as stealthy on switches occur most often when the DNA is in an open shape, meaning the DNA in a specific region has lost some of its regulation and control features. Such sections of the genome are no longer closed off and shut down as they should be.
As such, finding ways to lock down DNA that has opened up inappropriately could lead to new types of cancer drugs.
Wang also says the study provides information that could help doctors predict a patient’s prognosis. For example, tumors with transposable elements acting as stealthy on switches are more aggressive than those that lack this type of cancer gene activation, and that information could guide treatment decisions with therapies that are already available.
“A lot of what transposable elements are doing in our genome is still a mystery,” Wang says. “This study is the first detailed outline of their important roles in cancer. We hope this research provides new ways for scientists to approach the development of cancer therapeutics. Using knowledge of how genes are regulated, we hope to find ways to shut down these jumping genes that drive tumor growth.”
The study appears in the journal Nature Genetics. The National Institutes of Health; the American Cancer Society; and a Howard Hughes Medical Institute Medical Research Fellowship funded the work.
