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Rewriting Life

New Cancer Marker May Aid Earlier Detection

Repetitive stretches of RNA are found in high concentrations in cancer cells.

Compared with their healthy cousins, cancer cells are a chaotic mess, often having extra chromosomes, abnormal shapes, and other odd attributes. Now scientists have discovered a strange feature that appears to be unique to cancer cells: long stretches of repetitive RNA, known as satellites. Preliminary research suggests that the satellites appear early in the development of cancer, a finding that may ultimately aid early detection.

Early warning: Cancer cells contain high concentrations of repetitive stretches of RNA known as satellites (the dark stain indicated by an arrow in the bottom image), while healthy cells (top) do not.

“It’s a very interesting and provocative finding,” says Stuart Orkin, chairman of pediatric oncology at the Dana-Farber Cancer Institute, who was not involved in the research. “It suggests wholesale changes in gene expression in cancer cells that was previously unrecognized. It hints at how chromatin [the mass of DNA and proteins that make up chromosomes] and gene expression in cancer cells are deranged in a global fashion.”

David Ting, Daniel Haber, and collaborators at Massachusetts General Hospital discovered the markers by accident while Ting was studying RNA from tumor cells. The DNA that codes for genes is normally transcribed into RNA, which is then translated into proteins. Ting was puzzled by the appearance of RNA molecules whose sequence didn’t correspond to genes. He found that the sequences corresponded instead to satellites, stretches of repetitive DNA that are transcribed into RNA but never translated into proteins.

“We were surprised to find [the satellites] are expressed in abundant amounts in tumor tissue compared to normal tissue,” says Ting. Follow-up testing in both mouse and human cancer tissue revealed high levels of satellites in different types of tumors, including lung, kidney, ovarian, prostate, and pancreatic cancers.

“This is a fascinating finding because there is no precedent for finding a single class of [DNA] that is uniformly overexpressed in different types of cancer,” says Bert Vogelstein, professor of oncology and pathology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. “It appears to be true in virtually every cancer they looked at.”

While scientists have known about the existence of satellite repeats in the genome for years—they make up about five percent of the genome—the role they play in healthy cells is still unclear. “For a long time, people have ignored it, thinking it was residual DNA,” says Ting. In fact, most software used to analyze DNA sequences is designed to eliminate these stretches from their analysis, he says.

Scientists do know that satellites are expressed during fetal development, and they are thought to help chromosomes to divide normally. That similarity between cancer cells and embryonic cells—both can proliferate extensively—may hint at the role satellites play in cancer. “Somehow cancer has found a way to go backwards, to hijack a program from early in development for malicious use,” says Ting.

However, researchers don’t yet know whether satellites play a central role in the development of cancer or merely reflect some other malignant process. It might be analogous to, for example, prostate-specific antigen (PSA), which is found in high levels in prostate-cancer cells but doesn’t play a role in cancer. Either way, they hope the repetitive sequences will provide a new biomarker for diagnosing cancer.

If scientists confirm that satellite expression is highly concentrated only in cancer cells in adult tissue, they may be able to diagnose cancer accurately from very small amounts of tissue, such as the cells collected during needle biopsies. Ting’s team has already done some initial testing on cells collected in needle biopsies of pancreatic cancer. With a fluorescent molecular probe designed to bind to the satellites, “you can see cancer cells light up, while non-cancer cells do not,” says Ting. Currently, pathologists analyze cells based mainly on their appearance under the microscope, and their assessment can vary widely.

Ting’s team also found high concentrations of satellites in a type of precancerous cell that precedes pancreatic cancer. “That implies satellites are turned on relatively early in cancer development,” says Ting. If so, he hopes they can be used to detect cancer early. “Now we are trying to get a sense of the landscape. For what percentage of other cancers does this phenomenon occur? It seems to be prevalent, but we don’t have numbers.”

Researchers say they were able to make this discovery in part because of the type of sequencer they used—one from Helicos Biosciences that reads single molecules of DNA and RNA allowed scientists to count the number of RNA molecules present in the samples. Most other sequencers on the market have to replicate the RNA or DNA molecules under study before sequencing them.

Ting says he hopes other scientists will start to look for satellites in their own samples. “We think this is an initial step towards a new area of research for cancer,” he says.

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