Fatal Inheritance

Sidebar: Breaking the Genetic Curse

Breaking the Genetic Curse

Because of the threat of pancreatic cancer, Sheri Mayer must live the rest of her life as a diabetic.

Worse, she says, is that because of her family history, the lives of her children and future generations are at risk. But Mayer takes comfort in knowing that her doctor, Teri Brentnall, is also a groundbreaking researcher in the fight to find a cure for the deadly disease.

Earlier this year, Brentnall and a team of researchers from the University of Washington, Fred Hutchinson Cancer Research Center, and the University of Pittsburgh, announced a breakthrough in mapping the location of a gene associated with inherited pancreatic cancer. It is the first genetic defect linked directly to the disease.

"At least 10 percent of pancreatic cancer is hereditary, and by understanding that form of the disease we can also learn a lot about the non-hereditary form, which is far more common," says Brentnall. "There are about 100 genes in the region we've been searching, and we know we're getting close."

Brentnall says the genetic investigation is like looking for one house somewhere in the world. "You narrow it to somewhere in the Northwest," she says. "Then it's somewhere in the city. You keep narrowing it down, and then you have to find it."

In addition to Brentnall (a UW associate professor of medicine and pathology), the research team includes Leonid Kruglyak and Michael Eberle of Fred Hutchinson; and David C. Whitcomb and Rolan Pfutzer from Pitt.

With the assistance of an anonymous and wide-ranging Pacific Northwest family—dubbed "Family X"—Brentnall continues to gather data on the largest pancreatic cancer family ever researched. Twenty members of the family have been scrutinized, 18 of them with pancreatic cancer or pre-cancer, and two with pancreatic insufficiency.

"Five out of the six brothers in this family have died. Nine people in all," says Brentnall, who has followed "Family X" for seven years. "The cancer really hit this family early, most in their middle 40s, and it gets younger with each generation."

Brentnall says it is most common for people with a family history to be diagnosed in their 50s and 60s on the West Coast, and as late as their 70s in the East.

Using DNA samples that Brentnall's group collected from Family X, Pitt researchers genotyped hundreds of areas of the genome. This helped Kruglyak's team to show which genetic variations affect family members with pancreatic cancer or dysplasia (pre-cancer).

A specific genetic marker was found on nearly every member of Family X, all on the chromosome 4 arm, where the single-gene mutation responsible for pancreatic cancer is often found.

As a result, future generations of Family X will be more easily screened for the disease, perhaps a simple blood test being enough to determine if they have inherited the gene.

"We are hoping that the future may help us understand the genes that cause pancreatic cancer," says Brentnall, "and help us develop the drugs or vaccines that prevent its development."—Scott Holter

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