Pancreatic cancer years in the making

Decade elapses from first mutation to tumor formation, and years more until the disease spreads

The lead time for cancer of the pancreas to develop is extensive, possibly opening up a decade-long window of opportunity for doctors to someday screen for and remove tumors on this vital organ, a study in the Oct. 28 Nature shows. A companion study finds unusual chromosomal rearrangements in this deadly cancer, a characteristic that might provide insights into the cancer formation process.

Scientists have puzzled over the deadly nature of pancreatic cancer, in which fewer than 5 percent of patients survive for five years after being diagnosed. By then the cancer has usually spread beyond the pancreas to lymph nodes or other organs.

Some researchers argue that the cancer is so lethal because it is fast-growing and aggressive, while others suggest the cancer’s deadliness stems from an ability to remain hidden for years.  The new research suggests the slow-growth theory might be on target.

In 2008, cancer geneticist Bert Vogelstein and his colleagues at Johns Hopkins University in Baltimore published the complete genetic profiles of 24 pancreatic cancers, identifying more than 60 mutations common to the tumors. One of the new studies used those data to calculate the pace of cancer growth in the pancreas. Using that figure and the average cell proliferation rate in the organ provides a molecular clock of sorts with which scientists can figure out how long it has taken for the first cancer-related mutation in a pancreas cell to develop into cancer.

In pancreatic tumors obtained in autopsy from seven patients, that interval turned out to be an average of 11.7 years. It took another 6.8 years on average for tumors to appear outside the pancreas. Martin Nowak, a mathematician and evolutionary biologist at Harvard University, contributed the mathematical model that enabled the team to probe backward in time.

“We were surprised and very pleased by this result,” Vogelstein says. This long lead time might eventually enable doctors to spot genetic or protein abnormalities linked to the cancer, he says.

Doctors might also find it worthwhile to scan the pancreas using ultrasound for signs of a tumor in patients at risk, says study coauthor Christine Iacobuzio-Donahue, a pathologist and cancer researcher also at Johns Hopkins University. For example, during a routine endoscopy doctors view the stomach with a camera-tipped tube threaded down the throat. Adding an ultrasound attachment could scan the nearby pancreas for aberrant growths, she says. Cancer confined to the pancreas is often treatable with surgery, she notes.

In the other study, Iacobuzio-Donahue teamed with British researchers to explore the nature of chromosomal instability in pancreatic tumors from 13 patients. The researchers found that these patients often had a distinct pattern of chromosomal rearrangements called fold-back inversions, in which strings of DNA are looped and folded back upon themselves. Where the strings bent they snapped, Iacobuzio-Donahue says, and reattached. The origin and consequences of these rearrangements are unclear, but their pattern appears different from such rearrangements seen in breast cancer, the researchers note.

“The two studies are a bellwether, and are among the first to explore the biological and clinical implications of [genomic] sequence data for individual tumors,” says E. Georg Luebeck of the Fred Hutchinson Cancer Research Center in Seattle, writing in the same issue of Nature. “It is hoped that such information will not only deepen our understanding of the cancer process, but also lead to new approaches to early cancer detection, better prognosis and, ultimately, prevention.”

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