Finding pancreatic cancer's "address"

Collaboration produces genetic discovery, fuels hope to prevent, detect and treat deadly enigma
Dr. Teresa Brentnall and nurse Sharon Burke prepare to insert an endoscope tube.
Dr. Teresa Brentnall (right), a University of Washington gastroenterologist, along with UW endoscopy nurse Sharon Burke, prepares to insert an endoscope tube in the mouth of a patient. Brentnall, Hutch researcher Dr. Leonid Kruglyak and University of Pittsburgh gastroenterologist Dr. David Whitcomb recently reported the discovery of the first genetic defect linked directly to pancreatic cancer. Photo by Clay Eals

The first genetic defect linked directly to pancreatic cancer has emerged from a study by Dr. Leonid Kruglyak of the Human Biology and Public Health Sciences divisions and collaborators at the University of Washington and University of Pittsburgh.

Kruglyak, a statistical geneticist; Dr. Teresa Brentnall, a UW gastroenterologist; and Dr. David C. Whitcomb, head of gastroenterology at Pitt; reported their findings in the early electronic edition of the April issue of the American Journal of Human Genetics. Dr. Michael Eberle, a staff scientist in Kruglyak's lab, was a lead author.

Kruglyak's team performed the genetic-data crunching that mapped the gene to the long arm of chromosome 4. Having found the gene's neighborhood, in a fairly large region called 4q32-34, the researchers aim to close in on its specific address.

"There are about 100 genes in the region, a fair amount of data to sift through, said Brentnall, UW associate professor of medicine and pathology. "I would think we'd probably have the gene sequenced within a year, but ultimately it's truly a matter of luck."

Finding the gene promises to shed new light on how pancreatic cancer develops, ultimately opening new avenues for preventing, detecting and treating a deadly malignancy that has, until now, largely remained an enigma in cancer research.

"You can't touch it or feel it. You can't find it on physical exam. The cancer is asymptomatic, strikes later in life and is rapidly lethal. Most people die within six months of diagnosis," Brentnall said.

'Previously a black box'

"Such factors have impeded the collection of material for study and have hampered our ability to understand the natural history of the disease, resulting in very little headway in the past 100 years. This finding will open up an area that was previously a black box."

Gathering enough genetic data to help pry open that box was made possible, first and foremost, by the cooperation of a large Northwestern clan widely known in scientific circles as "Family X," the largest pancreatic-cancer family ever studied.

"What makes this family so remarkable is that it is extremely large and has a high incidence of early onset pancreatic cancer. Most family members have been diagnosed in their mid-40s, and the age of diagnosis just keeps getting younger with every generation," said Brentnall, who has been working with Family X, scientifically and clinically, for more than seven years.

Of 20 affected family members studied (18 with pancreatic cancer or evidence of precancerous changes, called dysplasia, and two with a condition called pancreatic insufficiency), nine have died of the disease, including five out of six brothers.

"Not a good family to be a member of in this regard," said Kruglyak, who also has lost a family member to the disease, a cousin to whom he dedicates his work on the project.

But Family X is an excellent family for studying inherited pancreatic cancer, which accounts for about 10 percent of such malignancies.

"Other pancreatic-cancer families that have been studied have been too small to be informative, as they tend to have just one or two affected individuals," said Kruglyak, who also serves as a Howard Hughes Medical Institute investigator.

Pioneer screening program

Another crucial aid to data collection was the development of a pioneering, UW-based, pancreatic-cancer screening program for high-risk individuals that uses endoscopic imaging techniques to help detect precancerous changes in the pancreas while there's still time to intervene surgically - before cancer develops.

All members of Family X who have had abnormalities detected endoscopically - and have had precancerous changes confirmed through tissue biopsy - have opted for preventive removal of the pancreas.

Those who undergo pancreatotomy must take insulin and digestive enzymes for the rest of their lives to compensate for the organ's removal. Though all of these patients become insulin-dependent diabetics, they can enjoy long, productive lives, said Brentnall, founder and director of UW's pancreatic-cancer surveillance program, the first of its kind in the nation.

The program serves 35 patients from more than a dozen families. Similar screening programs are now in place at several other institutions, including Johns Hopkins and the Mayo Clinic.

DNA samples collected by Brentnall's group from Family X were genotyped by a team of Pitt researchers led by Whitcomb, professor of medicine, cell biology and physiology, and human genetics, and director of the university's Center for Genomic Sciences.

In genotyping, Whitcomb and colleagues sequenced DNA from hundreds of areas of the genome known to contain a high degree of genetic variability. This information then served as a reference point for Kruglyak's team, which provided linkage analysis, using sophisticated computer software to determine which genetic variations are always present in family members with pancreatic cancer or its precursor, dysplasia.

Virtually every member of Family X with pancreatic cancer or dysplasia was found to harbor a specific genetic marker on the long arm of chromosome 4, where the single-gene mutation responsible for pancreatic cancer is thought to lurk. Equally important, none of the unaffected family members inherited this marker, a testament to its clinical and statistical significance.

Finding this marker would not have been possible without the tri-institution collaboration, Whitcomb said.

"Those of us who work with complex and mysterious medical problems like pancreatic cancer recognize that no independent physician or scientist can go from the bed to the bench and back again alone," he said. "It takes physician-scientist teamwork, as demonstrated here, to make the big breakthroughs."

Promise for screening

While this scientific break ultimately may lead to the discovery of a specific pancreatic-cancer gene, already it shows promise for screening the disease in future generations of Family X.

"Just having these markers, in principle, has diagnostic implications for this specific family," said Kruglyak, also an affiliate professor of genome sciences at the UW School of Medicine. "With a simple blood test, we should at least be able to tell, with good confidence, whether new members of this family are likely to have inherited the gene.

"Once the actual gene is found, if it turns out to be commonly mutated in all forms of pancreatic cancer, not just the inherited type, it could be used as a marker for broad screening. Knowing and understanding the gene's pathways to cancer also could lead to new therapeutic developments."

Study support came from the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Mental Health; the National Pancreas Foundation; the Lustgarten Foundation; the Center for Genomic Sciences, University of Pittsburgh; and the Chiron Corporation.

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