The complete genetic blueprint for lethal pancreatic cancer
and brain cancer has been deciphered by a
team at the
Johns
Hopkins Kimmel Cancer Center.
The studies, led by the same group that completed maps
of the breast cancer and colorectal
cancer genomes in 2007, are reported in two articles in the
Sept. 5 issue of Science Express.
Believed to be the most comprehensive result to date
for any tumor type, the new map
evaluated mutations in virtually all known human protein-
encoding genes, comprising more than 20,000
genes, in 24 pancreatic cancers and 22 brain cancers.
A core set of regulatory gene processes and pathways,
about a dozen for each tumor type, were
found to be altered in the majority of tumors studied by
the researchers. In pancreatic cancer, these
12 pathways, including those linked to DNA damage control,
cell maturation and tumor invasion, were
altered in 67 percent to 100 percent of tumors.
"This perspective changes the way we think about solid
tumors and their management because
drugs or other agents that target the physiologic effects
of these pathways, rather than individual
gene components, are likely to be the most useful approach
for developing new therapies," said Bert
Vogelstein, co-director of the Ludwig Center at Johns
Hopkins and a Howard Hughes Medical Institute
investigator.
In addition to the pathway discoveries, a number of
individual mutated genes were identified,
including 83 cancer genes in pancreatic cancer and 42 in
the most lethal form of brain cancer,
glioblastoma multiforme, or GBM. Additionally, 70 genes
that were dramatically overexpressed in
either cancer encode proteins that are on the surface of
cells or secreted, making them potential
diagnostic and screening targets.
One gene, isocitrate dehydrogenase 1, or IDH1, was
found to be frequently mutated in a subset
of GBM brain cancers. The mutations were significantly more
common in young GBM patients, and were
associated with improved survival. IDH1 mutations were also
found in nearly all cases of secondary
GBMs (cancers that progress from pre-existing lower-grade
tumors), raising the possibility that this
mutation may be a useful marker for identifying which
low-grade brain tumors are most likely to
develop into the lethal GBMs.
Victor Velculescu, associate professor of oncology,
said that "patients with IDH1 mutations
seem to be different from other patients with GBM, both
clinically and biologically. It is conceivable
that these patients will ultimately benefit from different
treatments, potentially by targeting IDH1."
"The landscape of human cancers is clearly more
complex than has been previously appreciated.
Fighting it is going to be more of a guerilla war than a
conventional one because there are dozens of
mutated genes in each tumor," said Kenneth W. Kinzler,
co-director of the Ludwig Center at Johns
Hopkins and professor of oncology. "Individually, these
mutations don't seem formidable. But working
together, they form an enemy that will require us to
develop novel strategies to combat them, and the
best long-term strategy may be early detection of tumors,
when the number of guerilla warriors is
still small and more easily handled."
To make their findings, the investigators integrated
several methods of genetic analysis. They
used high-density microarrays to identify copy number
alterations (amplifications and deletions) and
next-generation sequencing technologies to evaluate gene
expression. They also developed novel
statistical algorithms to integrate these complementary
genetic analyses, as well as techniques to
separate alterations likely to contribute to cancer
initiation and progression from so-called passenger
mutations, which accumulate harmlessly during cancer
development.
Each project cost more than $4 million, with lead
funding for the Goldman Pancreatic Cancer
Genome Initiative coming from the Sol Goldman Charitable
Trust and Lillian Goldman Charitable Trust.
The Virginia and D.K. Ludwig Foundation provided lead
funding for the brain cancer project. The
Ludwig Brain Tumor Initiative represents the first formal
collaboration of Ludwig Centers established
by the Ludwig Fund in 2006.
This year an estimated 38,000 people in the United
States will develop pancreatic cancer, with
overall survival rates less than 5 percent. Although fewer
patients are diagnosed with brain cancers
(approximately 20,000 cases per year in the United States),
the results are equally catastrophic.
Ralph Hruban, director of the Sol Goldman Pancreatic
Cancer Research Center at Johns
Hopkins, said, "The main reasons we chose to focus on these
cancers is because they are so deadly and
have such limited treatment options. What we learn about
these tumors may lead to improved
diagnostic measures or therapies in the future."
The Lustgarten Foundation provided significant funding
for the pancreatic cancer research.
Additional funding came from the Virginia and D.K. Ludwig
Fund, Susan G. Komen Foundation, Michael
Rolfe Pancreatic Cancer Foundation, Joseph C. Monastra
Foundation, family and friends of George
Rubis, Viragh Family Foundation, Broad Foundation, Emerald
Foundation and National Institutes of
Health.
Additional support for the brain cancer research came
from the National Institutes of Health,
Pew Charitable Trusts, Pediatric Brain Tumor Foundation
Institute, Clayton Fund, Hirschhorn
Foundation, Alex's Lemonade Stand Foundation, American
Brain Tumor Association, American Society
of Clinical Oncology and Brain Tumor Research Fund.
Under separate licensing agreements between The Johns
Hopkins University and Genzyme,
Beckman Coulter and Exact Sciences corporations, Kinzler,
Vogelstein and Velculescu are entitled to a
share of royalties received by the university on sales of
products related to research described in
this paper. These authors and the university own Genzyme
and Exact Sciences stock, which is subject
to certain restrictions under university policy. The terms
of these arrangements are managed by the
university in accordance with its conflict-of-interest
policies.