Cancer researchers have discovered a new genetic abnormality in tumor cells that sets them apart from normal cells. In mice and humans, cancer cells cranked out large amounts of a specific type of RNA that had been ignored until now. The discovery could shed light on how cancer develops, and it could give pathologists a new marker for detecting cancerous cells in a biopsy.
Postdoctoral researcher David Ting and colleagues in the lab of cancer geneticist Daniel Haber of Massachusetts General Hospital in Boston found their new marker by using a next-generation sequencing machine to measure the RNA molecules, or transcripts, that are encoded by a cancer cell's DNA. Unlike traditional microarrays dotted with DNA probes that measure the activity of a subset of a cell's 20,000 genes, this "digital" gene expression analysis tallied all RNA transcripts.
To the scientists' surprise, a sizable fraction of the RNA transcripts in the first sample they tested—a mouse pancreatic tumor—were encoded by a type of DNA sequence called satellite repeats. These are short, repeated stretches of DNA that don't code for proteins. Because satellite repeats weren't considered important, microarrays don't test for their expression, Haber says.
In eight of 10 mouse pancreatic tumors, the level of satellite transcripts was a stunning 40-fold higher than in normal mouse pancreatic cells, the team reports online today in Science. The findings were similar in human tumors: high levels of a particular satellite RNA in 15 of 15 human pancreatic cancers, as well as in a small sample of prostate, lung, kidney, and ovarian tumors when compared with normal human cells.
When Haber's team stained this satellite RNA in pancreatic tissue that had been removed for biopsy, they showed that the cancer cells clearly stood out (see image), even in early stages of the disease. The marker could help improve cancer diagnosis, the researchers say. Often, doctors who suspect cancer in an organ will use a needle to collect a few cells and examine their shape. Although this test is less invasive than a surgical biopsy, it's not as accurate—Ting says that only 60% to 80% of pancreatic samples obtained in this way are correctly diagnosed. Pathologist Ralph Hruban of the Johns Hopkins University School of Medicine in Baltimore, Maryland, who says the cell staining is "pretty impressive," agrees that it could help with biopsies that are difficult to interpret.
Haber's group hopes to use the marker to improve their circulating tumor cell (CTC) chip, a device that captures cancer cells floating in a sample of a patient's blood. The method relies on protein markers to distinguish cancer cells from normal cells trapped by the chip, but no existing markers cut across cancer types. (Although cancer cells always carry mutations and abnormally expressed genes, until now no single genetic glitch distinguished cancer cells from normal cells.) "This seems to be so dramatically different," Haber says. However, his group hasn't yet worked out how to detect satellite RNA in the cells trapped by a CTC chip.
Down the road, the high levels of satellite expression could help reveal how cancer develops. "It's surprising and it means something. But at this point we don't know what it means," says cancer biologist Tyler Jacks of the Massachusetts Institute of Technology in Cambridge. Haber's group found that the high RNA levels correlate with the expression of certain genes involved in embryonic development—suggesting that cancer could be using normal developmental programs to evolve. But the researchers still need to figure out why the satellite RNA levels are so high and whether they contribute to cancer or are just a side effect of some other process.