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Genetic Pathways to Curable and Incurable Forms of Pancreatic Cancer Identified

Pancreatic ductal adenocarcinoma is an almost uniformly fatal disease regardless of the stage at time of diagnosis. However, a small percentage //of patients develop a form of ductal adenocarcinoma associated with cystic lesions that can be detected earlier, is less aggressive and has a 50 percent long-term survival rate. Why cystic ductal pancreatic cancer behaves differently, despite carrying the same basic genetic mutations as the more common and deadly type of ductal pancreatic cancer, has long been a mystery. Now researchers at Fred Hutchinson Cancer Research Center have unlocked the genetic reason why.

Using unique mouse models to mimic the progression of both forms of human pancreatic cancer, researchers have discovered that a specific sequence of otherwise common genetic mutations is responsible for sending cells down the less-traveled path toward cystic pancreatic cancer versus the well-traveled route to the more fatal form of ductal pancreatic cancer.

Sunil Hingorani, M.D., assistant member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, led a study to be published in the March 12 issue of the journal Cancer Cell that 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."

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