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Genetic pathways to curable and incurable forms of pancreatic cancer identified

> The findings reported in the journal by Hingorani and colleagues represent an accidental discovery. The researchers started out studying the common genetic pathways to pancreatic ductal adenocarcinoma in hopes of finding 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.

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, lead 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.

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Source:Fred Hutchinson Cancer Research Center


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