Gene mutation identified for aggressive form of pancreatic cancer

A mutated gene common to adenosquamous carcinoma (ASC) tumors has been identified. It is the first known unique molecular signature for this rare, but particularly virulent, form of pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, with roughly 45,220 new cases diagnosed and more than 38,400 deaths annually. Both numbers are rising. ASC cases are infrequent, but typically have a worse prognosis and higher potential for metastasis than more common types of pancreatic cancer.

"There has been little progress in understanding pancreatic ASC since these aggressive tumors were first described more than a century ago," said co-senior author Miles F. Wilkinson, PhD, professor in the Department of Reproductive Medicine at the University of California San Diego and a member of the Institute for Genomic Medicine. "One problem has been identifying mutations unique to this class of tumors."

In their paper, published in Nature Medicine (2014; doi:10.1038/nm.3548), Wilkinson, co-senior author Yanjun Lu, PhD, of Tongji University in China, and colleagues report that ASC pancreatic tumors have somatic or nonheritable mutations in the UPF1 gene, which is involved in a highly conserved RNA degradation pathway called nonsense-mediated RNA decay or NMD. It is the first known example of genetic alterations in an NMD gene in human tumors.

NMD has two major roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA), which are the molecules that help transcribe genetic information into the construction of proteins essential to life. Second, it degrades a specific group of normal mRNAs, including those encoding proteins promoting cell growth, cell migration, and cell survival.

Loss of NMD in these tumors may "release the brakes on these molecules, and thereby driving tumor growth and spread," said Wilkinson.

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