Scientists at the Sol Goldman
Pancreatic Cancer Research Center at the Johns Hopkins
Kimmel
Cancer Center have used "personalized genome"
sequencing on an individual with a hereditary form of
pancreatic cancer to locate a mutation in a gene called
PALB2 that is responsible for initiating the
disease. The discovery marks their first use of a
genome-scanning system to uncover suspect
mutations in normal inherited genes.
The findings, they say, underscore the value of
so-called "personalized genome" sequencing,
which decodes a person's genes and compares the changes to
those found in healthy people.
"Gene sequencing has always had the potential to help
us learn if a person is susceptible to
certain diseases," said Alison Klein, director of the
National Familial Pancreas Cancer Tumor Registry
at Johns Hopkins. "By finding the genetic error responsible
for this patient's pancreatic cancer, our
team has provided an excellent example of the power of this
approach."
The coding error in PALB2 (which stands for "partner
and co-localizer of BRCA2") causes a
shortened version of the protein encoded by this gene,
rendering it incapable of working with another
cancer-related gene, BRCA2, to repair broken DNA. Mutations
in BRCA2 are also known to cause
hereditary forms of cancer.
Klein and her team caution that their finding has not
yet resulted in a clinical test for the
hereditary pancreas cancer gene, but laboratories at Johns
Hopkins and possibly elsewhere will be
developing one, which she says can be used to increase
cancer surveillance for early signs of disease in
those at risk.
Reporting their findings in the March 5 edition of
Science Express, the Johns Hopkins
researchers say that they sequenced genes taken from a
person with pancreatic cancer whose sister
also had the disease, suggesting an inherited
predisposition.
Sian Jones, research associate at the Johns Hopkins
Kimmel Cancer Center, said, "Generally, we
need data from very large families to identify the
inherited gene, and that was not available in this
case." Instead, the investigators used high-powered
computer software to scan all known protein-
coding genes in the patient — approximately 20,000 of
them — to find more than 15,000 variations.
Most of the variations were normal ones coding for
such things as eye or hair color, but the
search was designed to track down particular mutations that
caused certain proteins to be shortened,
a process that commonly occurs in cancer, said James
Eshleman, associate professor of pathology and
oncology.
The search yielded one gene variant, PALB2, resulting
from a substitution of a single DNA
letter coding for cytosine with a different one that codes
for thymidine.
The research team then scanned for the PALB2 gene in
96 other individuals with pancreatic
cancer who each had at least one relative with pancreatic
cancer. Three of them had coding errors in
the PALB2 gene that shortened the protein in a similar way.
Klein estimates that 3 percent of people
with hereditary pancreatic cancer have mutations in PALB2,
making it the second-most-common gene
mutation in these patients after BRCA2.
The investigators said they believe that their
approach could be used to identify inherited
alterations that predispose people to other types of
cancer, as well as to other genetic-based
diseases. "The more information we have about normal
variants, the easier it will be to find disease-
causing ones," said Michael Goggins, professor of
pathology, medicine and oncology at Johns Hopkins.
In the future, scanning genomes for hereditary
disease-causing genes could become "reasonably
routine," according to Bert Vogelstein, an investigator at
the Howard Hughes Medical Institute and
co-director of the Ludwig Center at Johns Hopkins.
The investigators say that the cost to determine the
sequence of all genes in an individual was
approximately $150,000 for this effort and that this cost
would likely decrease considerably in the
future.
Funding for the project was provided by the Lustgarten
Foundation for Pancreatic Cancer
Research, Sol Goldman Pancreatic Cancer Research Center,
Virginia and D.K. Ludwig Fund for Cancer
Research, National Institutes of Health and Michael Rolfe
Pancreatic Cancer Foundation.
In addition to Klein, Eshleman, Goggins and
Vogelstein, investigators who conducted the
research are Ralph Hruban, Mihoko Kamiyama, Michael Borges,
Xiaosong Zhang, D. Williams Parsons,
Jimmy Cheng-Ho Lin, Emily Palmisano, Keiran Brune,
Elizabeth Jaffee, Christine Iacobuzio-Donahue,
Anirban Maitra, Giovanni Parmigiani, Scott Kern, Victor
Velculescu and Kenneth Kinzler, all of Johns
Hopkins.
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