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

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 cancer 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 a mystery.

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 appeared 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."

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

The findings, that Hingorani and colleagues report, represent an accidental discovery. The researchers started out studying the common genetic pathways to pancreatic ductal adenocarcinoma in hopes of discovering clues to developing early detection biomarkers and possible treatments to halt the progression of the disease. The work involved activating the pancreatic cancer oncogene called Kras and then selectively mutating tumor-suppressor genes such as p53, p16 and Dpc4 in different combinations.

The path of improved survival

In the mouse model, which Hingorani first developed while at the University of Pennsylvania, the combination of Kras and p53 led to the more deadly form of pancreatic ductal adenocarcinoma. Earlier studies by researchers in Boston also found the same association between Kras and p16. From studies of human cancers, it is known that mutations in Dpc4 can also occur, but they do so late in the course of disease progression. The current study showed that the combination of Kras and an early mutation of Dcp4, in which one copy of the suppressor gene is eliminated, leads to cancer by a different path, beginning with the creation of a distinct class of precancerous lesions in the ductal epithelium called mucinous cystic neoplasms (MCN). This initiates a process that results in the rarer, but far less deadly, cystic pancreatic cancer.

MCN lesions often are large enough to be detected early by MRI or CT scan and also to cause symptoms. The cells in this cancer also react differently to a key signaling protein, TGFb, which can induce cancer cells to change shape and become more mobile and invasive. It turns out that the cystic pancreatic cancer cells are resistant to these effects of TGFb and these types of cancers are also less likely to invade surrounding tissues and to metastasize, or spread, to other organs. These properties likely contribute to the improved survival seen with this form of the cancer, Hingorani said.

Unraveling the deadly difference

Conversely, the initial lesions that lead to the more common and deadly form of pancreatic ductal adenocarcinoma, called pancreatic epithelial neoplasms, are tiny enough to be undetectable until the disease has progressed to the point where survival is almost nil. Moreover, these cells appear to be highly sensitive to the tumor-promoting properties of TGFb and thereby manifest a more aggressive behavior.

"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.

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

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.