CHAPEL HILL – A gene discovered by researchers at the University of North Carolina at Chapel Hill School of Medicine has been associated with two forms of pancreatic cancer, according to a study by an international group of researchers.
The gene, called palladin, was discovered six years ago by Dr. Carol Otey and her former student, Dr. Mana Parast, now a pathology fellow with Brigham and Women's Hospital in Boston. Otey has shown that palladin is involved in the formation of scar tissue on nerve cells in the brain or spinal cord, and it's found in cells that are moving, including embryonic cells and cells at the edge of wounds.
"Now we find it implicated in pancreatic cancer," said Otey, an associate professor of cell and molecular physiology at UNC and a member of the UNC Neuroscience Center.
A study reported in the Dec. 12 issue of PLOS-Medicine, led by scientists at the University of Washington and the University of Pittsburgh, found palladan overexpressed in people with sporadic, or non-familial, pancreatic cancer. A mutation of the gene was overexpressed in cells of people with familial pancreatic cancer, which makes up at least 10 percent of all pancreatic cancer cases. Otey is a co-author on the paper.
This discovery could lead to earlier diagnosis and more targeted treatments. In the United States, pancreatic cancer is the fourth leading cause of cancer death and the third leading cause of cancer death among people 40 to 59 years. Most people with the disease die within a year of diagnosis; about 95 percent of patients die within five years.
Palladin, which Otey named for 16th century architect Andrea Palladio, "is very involved in the architecture of cells, specifically via the actin cytoskeleton, a polymer protein complex that provides much of the basis for cell shape," Otey said.
In 1996 Dr. Teresa A. Brentnall, an associate professor of medicine at the University of Washington, became aware of a family in which 18 members, over four generations, died of pancreatic cancer. Subsequent DNA samples from this family, including from those with the initial stages of pancreatic cancer and those without the disease, led to the isolation of palladin on a particular region of chromosome 4.
Dr. Kay L. Pogue-Geile, assistant director of microarray at the National Surgical Adjuvant Breast and Bowel Project Laboratory in Pittsburgh, developed a customized DNA microarray to assess genes in that region of the chromosome and looked for gene overexpression or overactivity. Pogue-Geile and Brentnall share first authorship on the PLOS paper.
The analysis found a mutated palladin gene in all family members affected with early stage disease but not in those unaffected. The mutation was associated with gene overexpression 21 times greater than other genes in that region. Moreover, in pancreas cells of people with sporadic pancreatic cancer, the research team found palladin also overexpressed, and increasingly so, as the disease progressed.
The study team said these findings could account for changes in the cytoskeletal architecture of pancreatic cancer cells, and those alterations "may be responsible for the tumor's invasive and migratory abilities."
"We don't know how the palladin mutation found in this study contributes to the movement or invasiveness of cancer cells. That's the part of the story we still have to figure out," Otey said.
Other authors on the paper are Drs. Ru Chen, Kara White, and David Crispin at the University of Washington; Drs. David Whitcomb and Ryan George at the University of Pittsburgh; Dr. Mary Bronner at the Cleveland Clinic Foundation; and Drs. Tatjana Crnogorac-Jurcevic and Sally Dowen at The Barts the London School of Medicine and Dentistry.
Research support for Otey in this study came from the National Institute of Neurological Disorders and Stroke, a component of the National Institutes of Health.