Pancreatic-cancer survival: Clues from a genetic path less taken

Sunil Hingorani leads study that uncovers genetic sequence responsible for rare form of pancreatic cancer

Photo by Susie Fitzhugh Dr. Sunil Hingorani used mouse models to discover the genetic sequence that determines the development of either a deadly or a more curable form of ductal pancreatic cancer in humans.

Researchers at the Hutchinson Center now hold the key that unlocks genetic clues to the mystery separating the outcomes of two forms of pancreatic ductal cancer. Pancreatic ductal adenocarcinoma is an almost uniformly fatal disease regardless of the stage at the time of diagnosis. However, a small percentage of patients develop a form of ductal adenocarcinoma associated with cystic lesions that can be detected earlier. Cystic ductal pancreatic cancer is less aggressive and patients have a 50 percent long-term survival rate. Why cystic ductal pancreatic cancers behave differently, despite carrying the same basic genetic mutations as the more common and deadly type of ductal pancreatic cancer, has been the sealed secret.

Using unique mouse models to mimic the progression of both forms of human pancreatic cancer, Dr. Sunil Hingorani, of the Clinical Research and Public Health Sciences divisions, led a study that discovered a specific sequence of otherwise common genetic mutations is responsible for sending cells down the less-traveled path toward cystic ductal pancreatic cancer versus the well-traveled route to the more fatal form of ductal pancreatic cancer. The study, which appears in the March 12 issue of the journal Cancer Cell, explains this sequence and details why the cells behave differently.

"Although at their end stage the two different routes to ductal pancreatic cancer can look very much the same under the microscope, involve the same constellation of genetic events, and culminate in invasive and metastatic disease that can ultimately kill patients, one route is 100 percent fatal while the other is 50 percent curable," Hingorani said. "Until now we didn't understand why. What these studies suggest is that it's not just the total complement of mutations that determines the behavior of these cancers but also the sequence in which the mutations arise."

"With accurate animal models of both forms of pancreatic ductal cancers now in hand, it should be possible to unravel the detailed mechanisms behind their distinct behavior and hopefully identify points of vulnerability in the more fatal form to improve survival," Hingorani said.

About 5 percent of all primary tumors of the pancreas, out of 40,000 annual new cases in the United States, arise from cystic tumors.

The National Cancer Institute, the National Institutes of Health, an American Academy of Cancer Research and PanCAN Career Development Award and the Canary Foundation supported research for this paper.

Collaborators include scientists from the University of Washington School of Medicine, Abramson Cancer Center in Philadelphia, Sol Goldman Cancer Research Center in Baltimore, Harper Hospital and Wayne State University School of Medicine in Detroit, and the National Institutes of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.

To read more, visit www.cancercell.org.

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