Local family helps identify gene tied to deadly cancer

Scientists at the University of Washington have identified a gene important in the inherited form of pancreatic cancer, a discovery that caps a decade of research and could eventually lead to earlier diagnosis and treatment of one of the deadliest forms of cancer.

"I think it will play a major role in understanding of the disease," said Dr. Teri Brentnall, a UW associate professor of gastroenterology and senior researcher. "Now we have to dig to find out more about how the cancer happens."

Identifying the gene, which researchers have dubbed "palladin," involved extensive analysis of a Northwest family that has lost nine members over four generations to pancreatic cancer and has another nine members who have had early signs of the disease.

"I'm real excited about it," said Ryan Chappell, 21, of Lacey, Thurston County, a member of the family. "I feel really good that my family has not suffered [in vain]. Something has been accomplished from their contribution."

Rare but deadly

Cancer of the pancreas is relatively rare compared with other cancers, but it is the third-leading cause of cancer death among people age 40 to 60. The pancreas is a vital organ deep in the mid-body that produces digestive juices and insulin to help the body use sugar. Pancreatic cancer usually is not discovered until it has spread to other parts of the body.

About 33,700 people in the U.S. are diagnosed with the disease annually, and 32,000 die, including about 700 in Washington state. Nationally, only about 5 percent live longer than five years, according to the American Cancer Society.

Brentnall and her UW colleagues first identified the general region of the palladin gene in 2002 and pinpointed its location several months ago. With the UW's Ru Chen, co-lead author, and colleagues at four other medical centers, they publicly reported the discovery today in the online journal PLoS Medicine.

The gene makes a protein for the skeleton of pancreas cells, helping maintain their shape and anchoring them in the organ. Researchers found that in the cancer patients from Chappell's family, the gene was mutated and produced higher-than-usual amounts of the protein. The protein also is misshapen in the cells, allowing them to break free and move into other parts of the body.

"They're like a tumbleweed, rolling away," Brentnall said. "They migrate 50 percent faster than other cells. The fact that they move like that is a key feature in cancer."

Only 10 percent of pancreatic-cancer cases are thought to be inherited. But Brentnall and her colleagues found that the gene also produced higher-than-usual amounts of the palladin protein in patients with no family history of the disease, even though the gene was not mutated. They don't know why.

The scientists hope they can develop a diagnostic test to find excess amounts of the protein in the blood early in the disease. And they hope to develop a drug to somehow inhibit the protein and prevent the cancer cells from moving.

"We hope to exploit the palladin gene in any way we can," Brentnall said.

Dr. James Abbruzzese, a prominent gastrointestinal cancer researcher from the University of Texas, said the research is "really important and interesting."

He agreed it could help lead to new tests and treatment, but he said the research needs to be replicated in families that don't have as much pancreatic cancer as Ryan Chappell's family. That would rule out the possibility that the mutated gene is unique to the family that was studied.

Abbruzzese, like Brentnall, also wonders whether more than one gene is responsible for the cancer and what environmental factors might have an impact.

Breaking the curse

Chappell wishes a pancreatic-cancer test had been around long ago. It might have helped save his father, David, who died when Chappell was 7, and his grandfather, three uncles and several cousins.

"I so remember his gentleness and kindness," Chappell said of his father. "He was always smiling and happy, even when he was sick. I don't know how he did it."

Just three years after his father's death at age 33, Chappell was diagnosed with diabetes, a sign that his pancreas was failing. His doctors kept close tabs on him. But Chappell believed he was doomed, and he became chronically depressed and stopped regularly monitoring his blood sugar levels.

His eyes were damaged and he had nerve damage in his feet. His mother and other family members unsuccessfully urged him to take care of himself. Finally, he nearly died at age 19 when he blacked out and drove his pickup into the rear of a semi truck at 70 mph.

"It really turned me around. I decided I wanted to help my family and others by participating in this research" more fully, Chappell said.

Over the next year, tests showed Chappell's pancreas was on the verge of becoming cancerous, and surgeons removed it in a difficult operation. It took a year to recover fully, and he now must monitor his blood sugar even more closely. But he is working as a barista and plans to go back to community college soon.

Discovery of the gene, he hopes, will enable other families at risk for the cancer to stay on top of it and treat it early. "Maybe it will help break the curses in their families, too," he said.

For now, finding the cancer early is rare. The pancreas is deep in the body, and it is difficult to feel or see tumors through imaging. Symptoms — typically, jaundice, abdominal and back pain, and digestive problems — usually develop after the cancer has spread.

Brentnall pioneered a way of detecting the cancer in people from families with the disease: Patients swallow a flexible tube with a tiny ultrasound probe to get a better view of the pancreas, and pancreatic ducts are examined with dye and X-rays. Abnormal findings are followed by a biopsy, then removal of the pancreas if cancer is found.

About 15 patients at the UW and a few others at another medical center, all with inherited cancer, have had the string of procedures. Other patients are treated with chemotherapy and radiation.

Brentnall hopes the gene discovery will lead to quicker, easier diagnoses and less invasive treatments.

If funding is available and the research progresses well, she said, a diagnostic test could be developed in about five years, and a new treatment in about seven years.

Other institutions that participated in the research were the University of Pittsburgh, Cleveland Clinic, University of North Carolina and the London School of Medicine and Dentistry.

Warren King: 206-464-2247 or wking@seattletimes.com