Pancreatic Cancer Gene Mapped

Applied Genetics News,  March, 2002  

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Researchers at Fred Hutchinson Cancer Research Center (1100 Fairview Ave. N., P.O. Box 19024, Seattle, WA 98109-1024; Tel: 206/667-2896; Website: www.fhcrc.org) and the University of Washington School of Medicine, in collaboration with investigators at the University of Pittsburgh School of Medicine, have mapped the location of a gene associated with inherited pancreatic cancer.

Study directors Leonid Kulak, a Fred Hutchinson statistical geneticist; Teresa Brentall, a UW gastroenterologist; David C. Whitcomb, head of gastroenterology at Pitt; and colleagues report their findings in the early electronic edition of the April issue of the American Journal of Human Genetics. Michael Eberle of Fred Hutchinson and Roland Pfutzer of Pitt share first authorship of the paper.

"This is the first genetic defect that's been linked directly to pancreatic cancer," says Kruglyak, whose 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 now aim to close in on its specific address.

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

Finding the gene promises to shed new light on how pancreatic cancer develops, ultimately opening new avenues for preventing, detecting, and treating this particularly deadly malignancy, which 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," notes Brentnall. "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 hundred years."

Gathering enough genetic data 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. (The family chooses to remain anonymous.)

"What makes this family so remarkable is that it is extremely large and has a very 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," says Brentnall, who has been working with Family X, scientifically and clinically, for more than 7 yr.

Of the 20 affected family members studied (18 with pancreatic cancer or evidence of precancerous changes, called dysplasia, and two with a condition called pancreatic insufficiency), 9 have died of the disease, including 5 out of 6 brothers.

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

All members of Family X who've had abnormalities detected endoscopically-and precancerous changes confirmed through tissue biopsy-have opted for preventive removal of the pancreas, an organ that contains insulin-producing cells key to blood-sugar regulation. The organ also produces enzymes that aid digestion.

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

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 at Fred Hutchinson, who 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.

"Just having these markers, in principle, has diagnostic implications for this specific family," Kruglyak says. "With a simple blood test, we should at least now be able to tell, with good confidence, whether new members of this family are likely to have inherited the gene.

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