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Link to story entitled
Fatal Inheritance By Scott Holter
Can Families with a History of Pancreatic Cancer Stop a Genetic Time
Bomb? A Pioneering UW Program Can Help—But at a Price. June
2002
February 28, 2002
Region Narrowed for Pancreatic
Cancer Gene
Teri Brentnall, MD
Region Narrowed for Pancreatic Cancer Gene
News Brief
Reuter's Article
Pancreatic cancer is the fifth leading cause of cancer death in the
United States. Nearly every person diagnosed with pancreatic cancer will
die from it, usually within 6 months. Familial clustering of pancreatic
cancers occurs in at least 10% of all pancreatic cancer. However, the
late age of disease onset and rapid death of affected individuals
markedly hampers progress in determining the genes that are responsible
for pancreatic cancer. Dr. Brentnall and her colleagues have perform a
genetic linkage scan of a very large family that inherits pancreatic
cancer (Family X). We have developed an endoscopic surveillance program
(see above under surveillance) for this family that allows the early
detection of cancer and it’s precursor, before family members have died
of the disease. In a genome-wide screening of 373 microsatellite markers
we found significant linkage (maximum lod score 4.56 using two-point
analysis and 5.36 using three-point analysis) on chromosome 4, providing
evidence for a major locus for pancreatic cancer. The next step will be
to find the pancreatic cancer gene in this region.
The new pancreatic cancer susceptibility locus identified on
chromosome 4 is the first pancreatic cancer-specific genetic defect. All
of the known pancreatic cancer-associated genes and cancer syndromes
have been excluded by the location. The identification of a
susceptibility gene should shed new light on the mysteries that surround
pancreatic cancer. By understanding the identity of the gene, it is
possible to fully understand the underlying mechanism of why pancreatic
cancer forms and thus target chemotherapy accordingly. The discovery of
a familial pancreatic gene would allow identification of affected
families, and thus help to direct surveillance efforts to those who are
at highest risk (e.g. gene carriers). It is also likely that the gene
causing the familial form of the disease plays an important role in
pancreatic cancer found in the general population (sporadic form of the
disease). Finally, understanding the function of the gene may be the
cornerstone for chemoprevention efforts.
Advance by Fred Hutchinson, UW and Pitt collaborators made possible
with the help of "Family X" and a pioneering pancreatic-cancer screening
program that saves lives
SEATTLE - Researchers at Fred Hutchinson Cancer Research Center 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 Kruglyak, Ph.D., a Fred Hutchinson statistical
geneticist; Teresa Brentnall, M.D., a UW gastroenterologist; and David
C. Whitcomb, M.D., Ph.D., 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.
Other members of the research team include Michael Eberle, Ph.D., of
Fred Hutchinson and Roland Pfutzer, Ph.D., of Pitt, who shared first
authorship of the paper.
"This is the first genetic defect that's been linked directly to
pancreatic cancer," said Kruglyak, whose Fred Hutchinson 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," said Brentnall, UW
associate professor of medicine and pathology.
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," Brentnall said. "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.
"This finding will open up an area that was previously a black box,"
she said.
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. (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," said
Brentnall, who has been working with Family X, scientifically and
clinically, for more than seven years.
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), 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, an associate member of Fred
Hutchinson's Human Biology and Public Health Sciences divisions and a
Howard Hughes Medical Institute investigator.
Another crucial aid to data collection was the development of a
pioneering pancreatic-cancer screening program for high-risk
individuals, based at UW, 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'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, said Brentnall,
founder and director of UW's pancreatic-cancer surveillance program, the
first of its kind in the nation. The program currently 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.
The DNA samples from Family X collected by Brentnall's group 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 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.
Virutally 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
collaboration among the Fred Hutchinson, UW and Pitt researchers,
Whitcomb said. "Those of use 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. It takes physician-scientist teamwork, as demonstrated here, to
make the big breakthroughs."
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," Kruglyak said. "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.
"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," said Kruglyak, also an affiliate professor of
genome sciences at the UW School of Medicine.
Of the 29,000 Americans who this year will learn they have pancreatic
cancer, 28,900 will die within 12 months of diagnosis. While pancreatic
cancer is the fifth leading cause of cancer death in the United States,
it is one of the least well-funded areas of cancer research.
Support for this study was provided by 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.
Reuters: Scientists Narrow Pancreatic Cancer Gene
Search
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To obtain a copy of the paper, "A new susceptibility locus for
autosomal dominant pancreatic cancer maps to chromosome 4q32-34," go to
the American Journal of Human Genetics Web site,
www.ajhg.org/journal/.
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