December 12, 2006
UW-led team discovers gene for inherited pancreatic cancer
An international group of researchers has discovered that the mutated form of a gene called Palladin causes familial pancreatic cancer. The findings, published online December 12 in the journal PLoS-Medicine, may help explain why the disease is so deadly. The research project was led by Dr. Teri Brentnall, University of Washington associate professor of medicine, and supported by The Lustgarten Foundation, Canary Foundation, and other private sources.
Pancreatic cancer is usually a fatal diagnosis. One of the deadliest types of cancer, it is the fourth leading cause of cancer deaths overall, and third-leading cause of cancer deaths for people aged 40 to 60 in the United States. Most people with the disease die within a year of diagnosis; about 95 percent of patients die within five years. Researchers estimate that at least ten percent of all pancreatic cancer cases are inherited.
The discovery also reveals that the Palladin gene behaves abnormally in both the hereditary and non-hereditary, or sporadic, forms of pancreatic cancer. Previous studies by co-author Dr. Carol Otey, associate professor of physiology at the University of North Carolina, have revealed that when the Palladin gene is functioning properly, it gives a cell its shape and enables the cell to move. In the case of pancreatic cancer, a mutation in Palladin allows the cell to move much more quickly than normal, essentially invading the surrounding, healthy tissue.
Palladin, identified six years ago by Otey, is involved in the cytoskeleton, the structural backbone of all human cells. Brentnall discovered that Palladin played a role in pancreatic cancer and began to collaborate with Otey. The team believes that the mutated Palladin causes cancer by causing the cytoskeleton to malfunction, which allowed the cells to move much more quickly than normal cells.
“A normal cytoskeleton holds up the cell wall, and gives it direction to sit down in its proper place and basically to behave,” said Brentnall. “In cancerous cells, the cytoskeleton doesn’t work correctly, and instead of sitting, the cells get up and invade areas where they don’t belong, which is how the cancer spreads. This is a new way of thinking about cancer development in the pancreas.”
“Brentnall and her colleagues’ report of their fascinating discovery of a new cause of inherited pancreatic cancer provides us with important new insights into the mechanisms of pancreatic cancer development that will have a significant impact on future research,” said Michael Goggins, MD, Associate Professor of Pathology, Medicine and Oncology at The Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins.
Brentnall began her search for the pancreatic cancer gene in 1996 when one of her patients described his family’s “curse.” His grandfather, father, four uncles and three cousins had all died of pancreatic cancer, some at a very young age. Brentnall designated this family as “Family X” and set off to identify the source of the fatal inheritance. The puzzle took a decade to unravel.
Brentnall and her colleagues developed a surveillance program for the early detection of pancreatic pre-cancer in families who inherit the disease. “By performing surveillance on many of the Family X members, the research team identified which ones had the initial stages of pancreatic cancer” said Brentnall. “We then compared DNA samples from the family members with pre-cancer to those who did not have the disease, and isolated the cancer-causing gene to an area of Chromosome 4.”
Over the next two years, the researchers, led by Dr. Kay Pogue-Geile, associate professor of research at University of Pittsburgh School of Medicine, created a customized DNA microarray to help them isolate the gene responsible. They searched for the genes most abnormally expressed in that area on Chromosome 4, using pre-cancerous tissue from Family X pancreas and from 10 sporadic pancreatic cancers, comparing the results to normal pancreas tissue. The scientists hoped this approach would help them find the genes that were over-expressed in abnormal pre-cancerous and cancerous tissue.
“We finally found what we had so doggedly pursued — a gene that was expressed 21 times more than any other,” said Brentnall. “This gene, Palladin, was mutated in Family X and appeared to cause the fatal inheritance. Every one of the members of Family X who had the Palladin mutation got pancreatic cancer or pre-cancer, while the members of Family X who did not have the mutation were cancer-free.”
By understanding the genes that cause pancreatic cancer in families, scientists can better understand why the disease forms sporadically in the general population. When Brentnall and her colleagues examined pancreas cells from cancer patients with no family history, they found that Palladin was also over-expressed in those cells. In fact, they found that in these non-hereditary cases, the gene became increasingly over-expressed as the pancreas tissue progressed through the pre-cancer stage and then to cancer.
Testing for a Palladin gene mutation may be possible in families that inherit pancreatic cancer (two or more affected family members). However, genetic testing is not likely to be useful for non-hereditary or sporadic pancreatic cancer (only one person affected in a family). Brentnall and her team hope to develop a screening blood test for pancreatic cancer using the Palladin protein, as well as treatments that target mutations in Palladin. In addition, early indications show that the study of Palladin may also shed light on how and why other cancers spread as well. Further information regarding genetic testing can be obtained at http://www.uwgi.org/.
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Additional Information on Brentnall’s Research
Research funding
During the ten years that it took to complete this work, there were often periods of financial hardship –Brentnall almost stopped the research twice for lack of funding. “If not for the private support provided by The Lustgarten Foundation, and subsequently by the Canary Foundation and the Walters family, this important work would never have been completed,” said Brentnall. “I thank them, Family X thanks them, and people who might be saved in the future from pancreatic cancer thank them.”
Dr. Robert Vizza, President of The Lustgarten Foundation, which is the largest private funder of pancreatic cancer research, praises Brentnall’s work. “Dr. Brentnall and her team have given hope to those who are at-risk from familial pancreatic cancer. We are pleased to have played a role in supporting her breakthrough research which, we believe, could lead to further breakthroughs in the diagnosis, prevention and management of this killer disease.”
“Teri’s research delivers an important milestone in the growing recognition that early detection of cancer should become a national priority,” said Don Listwin, Founder of the Canary Foundation. “Her team’s work deserves the commitment of substantial resources from the NIH/NCI to deliver on the exciting potential of this discovery.”
Team of Scientists
The international team of scientists that made the discoveries was led by University of Washington researcher Dr. Teri Brentnall, an associate professor of medicine (bio attached), herself a breast cancer survivor. These close investigators have a diversity of scientific expertise which made this complex discovery possible.
Most of the work was done by eight women from several academic centers:
- Ru Chen, PhD; Kara White; Teri Brentnall, MD; University of Washington, Seattle
- Kay Pogue-Geile, PhD; University of Pittsburgh
- Mary Bronner, MD; Cleveland Clinic Foundation
- Carol Otey, PhD; University of North Carolina, Chapel Hill
- Tatjana Crnogorac-Jurcevic; MD, PhD; Sally Dowen, PhD; Barts and the London School of Medicine and Dentistry in London
The Future of This Research
The role of the cytoskeleton, and specifically the gene Palladin, will be a novel avenue for cancer research. Researchers now need to study how Palladin behaves abnormally in sporadic pancreatic cancer and exactly what mechanism allows the cells to become invasive.
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Questions and Answers on pancreatic cancer
Why is pancreatic cancer so deadly?
The pancreas is an organ deep within the body. It is located in the abdomen, right in front of the spine. Unfortunately, because of the location of the pancreas, most patients do not develop symptoms until the disease is advanced. By the time the cancer is detected it has escaped the local region of the pancreas and it spreads very rapidly into adjacent organs or regional lymph nodes, and/or systemically to the liver, lungs, and beyond. Compounding the problem, pancreatic cancer is not very responsive to chemotherapy or radiation. Surgery can occasionally cure pancreatic cancer, but usually only in cases where the tumor is very small. Only 25% of cancer patients are candidates for surgical treatment. Currently, there is no screening blood test for pancreatic cancer. It is rare for a person diagnosed with pancreatic cancer to achieve a cure.
What is Familial Pancreatic Cancer?
Pancreatic cancer is inherited in at least 10% of cases; the risk of a person developing pancreatic cancer is increased threefold if they have one first-degree relative who has the disease. Having multiple affected members increases the risk even more, so that some family members have a 50-50 chance of inheriting pancreatic cancer. The term Familial Pancreatic Cancer is used for families that have two or more family members with pancreatic adenocarcinoma (the most common kind of pancreatic cancer).
Is there pancreatic cancer surveillance for patients who have Familial Pancreatic Cancer?
Surveillance strategies for detecting early pancreatic pre-cancer are now unfolding. Surveillance would only be appropriate for patients who are at a very high risk of pancreatic cancer because they have at least two family members with the disease. All pancreatic cancer surveillance should be performed at a medical center with expertise in management of pancreatic cancer and pre-cancer. Surveillance programs differ throughout the United States: some recommend removal of the pancreas when high-grade pre-cancer is present, other programs wait until cancer or a mass has formed in the pancreas. Currently, the few published studies examining the best modalities for pancreatic cancer surveillance are from two centers: the University of Washington Medical Center and Johns Hopkins. In general, the surveillance programs are performed by gastroenterologists using two types of tests: endoscopic ultrasound (EUS) and endoscopic pancreatography. Both of these tests give a close view of the pancreas; however the findings, even when abnormal, are not necessarily diagnostic of cancer or pre-cancer. In order to make a diagnosis, a sample of the pancreas tissue must be evaluated by an experienced pathologist. If the EUS and pancreatography tests are abnormal and the pancreas has histologic evidence of carcinoma in-situ, cancer or a mass– removal of the pancreas could be considered in highly selected patients. Timing is crucial for determining when a patient warrants surgery, if performed too early the patient is put at risk for the morbidity and mortality of a pancreatectomy, including death and brittle diabetes. The alternative of diagnosing too late could lead to a patient with pancreatic cancer.
What are risk factors for Pancreatic Cancer?
- There are several risk factors for pancreatic cancer: family history, cigarette smoking, adult onset diabetes, and hereditary and chronic pancreatitis. Diet and the environmental exposures can also play a role.
- Family History– People who have immediate family (mother, father, or siblings) that have been diagnosed with pancreatic cancer are three times more likely to also be diagnosed. Each additional family increases the risk approximately 1.5 fold. A family history of colon or ovarian cancer also increases the risk of pancreatic cancer.
- Chronic pancreatitis increases the risk of developing pancreatic cancer by twofold.
- Smoking is associated with approximately 25 percent of pancreatic cancers. People who smoke for 20 years or more have double the risk of those who have never smoked. Smoking has an even greater effect in families that inherit pancreatic cancer—increasing the odds of developing cancer by up to sevenfold and patients who smoke tend to develop cancer at an earlier age. This cancerous effect of smoking is also seen in patients with chronic pancreatitis or hereditary pancreatitis.
- Diabetes – There is approximately a twofold increased risk of pancreatic cancer in patients who develop adult onset diabetes, especially those that are not obese.
- Diet – A diet high in fats and sugar has been linked to an increased risk of pancreatic cancers.
- Environment – Studies have shown that people with prolonged exposure to pesticides, dyes, petrochemicals, and other carcinogens are more likely to contract pancreatic cancers.
What does the pancreas do? Can you live without your pancreas?
The pancreas has two main jobs: one is to maintain even levels of blood sugar by secreting a hormone called insulin; the other job is to make and deliver the enzymes that help digest food. These enzymes are made in the pancreas and delivered into the small intestine where the food is digested. People can live without a pancreas, although they would not be able to control their blood sugars (diabetes) and would require insulin injections and enzyme tablets to help digest food.
How does pancreatic cancer grow?
Pancreatic cancer starts out in the pancreatic ducts. Pancreatic ducts are a set of tube-like structures that help the pancreatic enzymes to reach the small intestine– so that food can be digested. As pancreatic cancer grows, the tumor may invade organs that surround the pancreas, such as the stomach or small intestine. Pancreatic cancer cells may also break away from the tumor and spread to other parts of the body. When pancreatic cancer cells spread, they often form new tumors in lymph nodes and the liver, and sometimes in the lungs or bones. The new tumors have the same kind of abnormal cells and the same name as the original (primary) tumor in the pancreas. For example, if pancreatic cancer spreads to the liver, the cancer cells in the liver are pancreatic cancer cells. The disease is metastatic pancreatic cancer; it is not liver cancer.
How cancer initially starts in a pancreatic cancer cell is still under investigation. An accumulation of genetic changes are known to occur that parallel the increasingly cancer-like appearance of the cells. The pancreatic duct cells become larger and more abnormally shaped as they turn into pre-cancer. The cells begin to pile up and eventually develop the ability to invade into surrounding tissues. This is a key feature of cancer.
