February 28, 2002
Progress in Search for Genetic Trigger of Pancreatic Cancer
Researchers are reporting progress in the search for a gene mutation
that triggers pancreatic cancer, the fifth leading cause of cancer
death in the United States. Genetic studies of a family that has a long
history of pancreatic cancer have led researchers to a region of
chromosome 4 that is the likely location of a gene mutation that causes
cancer in members of this family.
Pancreatic cancer is difficult to detect, spreads quickly, and kills
almost all affected patients within six months of diagnosis. Of an
estimated 29,200 cases of pancreatic cancer diagnosed each year in the
United States, 28,900 patients succumb to the disease, usually within
four to six months of diagnosis.
“From these data, it became clear that four generations ago one man with this inherited locus passed the gene it contained on to five of his six sons, all of whom died of pancreatic cancer, but not before they passed it on to future generations.”
Leonid Kruglyak
Identification of the genomic region, or locus, on chromosome 4 that
contains the gene will be published in the April 2002 issue of the
American Journal of Human Genetics. The research team included
Teresa A. Brentnall of the University of Washington Medical Center,
Howard Hughes Medical Institute investigator Leonid Kruglyak and
Michael Eberle of the Fred Hutchinson Cancer Research Center, David C.
Whitcomb and Roland Pfützer of the University of Pittsburgh and
the VA Pittsburgh Health Care System.
One of the keys to finding the gene locus was Family X, whose
members have inherited a gene mutation that predisposes them to
pancreatic cancer. Brentnall and her colleagues have studied Family X
for more than seven years, observing that the pancreatic cancer usually
occurs in members of this family by age 43.
“There have certainly been cases of family clustering of
pancreatic cancer,” said Kruglyak. “But this is the largest
family yet found where pancreatic cancer segregates in a clearly
Mendelian fashion in an autosomal-dominant pattern.” Autosomal
dominance occurs when one of the two copies of a gene has a variation
that is sufficient for expression of a specific trait.
Pancreatic cancer has also been associated with hereditary
predisposition to other cancers — including some colon and breast
cancers and melanomas — as well as inflammatory pancreatitis. But
approximately ten percent of cases of pancreatic cancer are inherited
in an autosomal dominant fashion in families like Family X that
don’t have another disease.
As promising as the study of Family X appeared to be, Kruglyak said
that tracking members of the far-flung family, collecting blood samples
for analysis and monitoring the family for precancerous signs using
endoscopic techniques proved highly challenging. “It has taken a
lot of very hard work by Teri Brentnall and her colleagues to trace the
complex branches of this family and obtain material for study,”
he said.
Kruglyak, who made the decision to study pancreatic cancer after his
cousin died of the disease, set out to pinpoint the location of the
mutated gene carried by members of Family X. By doing detailed analysis
of genomic landmarks, called “microsatellite markers,” that
span the entire genomes of family members, Kruglyak and his colleagues
identified landmarks that were consistently passed down through the
generations along with the gene mutation that conferred a
predisposition to pancreatic cancer.
The scientists first analyzed a subset of the family to detect
regions of the genome that were consistently inherited together with
the disease. That initial study revealed that a region of chromosome 4
showed the best evidence of such “segregation.” The
researchers next added more family members and additional markers in
the target region, obtaining a highly significant association of
inheritance of the chromosome 4 region with the disease.
“We typed all of the available family members for the initial
and new markers just in that area, and we got a clear statistical
signal, way above chance, that this region cleanly segregated with the
disease,” said Kruglyak.
“From these data, it became clear that four generations ago
one man with this inherited locus passed the gene it contained on to
five of his six sons, all of whom died of pancreatic cancer,”
said Kruglyak. “But not before they passed it on to future
generations. And critically important, none of the unaffected
individuals in the family inherited this locus.”
The discovery of the pancreatic cancer susceptibility locus on
chromosome 4 has led to an intense effort to identify the specific gene
mutation that causes the disease, said Kruglyak. Identification of the
gene should be of immediate benefit to members of Family X because it
will enable earlier identification of family members who will develop
cancer later in life.
“So far, that’s the only direct impact,” he said.
“But we hope that once we pinpoint the gene, its identity will
suggest many more research avenues.” For example, he said,
spontaneous mutations in the susceptibility gene itself might play a
role in triggering sporadic, or non-inherited, pancreatic cancer. Also,
identification of the gene might reveal a pathway in which other
malfunctions may also cause the sporadic form of the disease. While the
existence of such a pancreatic cancer pathway is still speculative,
said Kruglyak, the genes involved in such a pathway might be targets
for drugs that could prevent pancreatic cancer.
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