The Cancer Genome Atlas Reports First
Results Of Comprehensive Study of Brain Tumors
The Cancer Genome Atlas (TCGA) Research Network, a collaborative
effort funded by the National Cancer Institute (NCI) and the National
Human Genome Research Institute (NHGRI) of the National Institutes
of Health (NIH), today reported the first results of its large-scale,
comprehensive study of the most common form of brain cancer, glioblastoma
(GBM). In a paper published Sept. 4, 2008, in the advance online
edition of the journal Nature, the TCGA team describes
the discovery of new genetic mutations and other types of DNA alterations
with potential implications for the diagnosis and treatment of
GBM.
Among the TCGA findings are the identification of many gene mutations
involved in GBM, including three previously unrecognized mutations
that occur with significant frequency; and the delineation of core
pathways disrupted in this type of brain cancer. Among the most
exciting results is an unexpected observation that points to a
potential mechanism of resistance to a common chemotherapy drug
used for brain cancer.
More than 21,000 new cases of brain cancer are predicted in the
United States this year, with more than 13,000 people likely to
die from the disease. GBM, which is the type of brain cancer most
often found in adults, is a very fast-growing type of tumor. Most
patients with GBM die of the disease within approximately 14 months
of diagnosis.
The TCGA network analyzed the complete sets of DNA, or genomes,
of tumor samples donated by 206 patients with GBM. The work complements
and expands upon a parallel study by Johns Hopkins researchers
of 22 GBM tumors, which was also published today in the journal Science.
"These impressive results from TCGA provide the most comprehensive
view to date of the complicated genomic landscape of this deadly
cancer. The more we learn about the molecular basis of glioblastoma,
the more swiftly we can develop better ways of helping patients
with this terrible disease,"said NIH Director Elias A. Zerhouni,
M.D. "Clearly, it is time to move ahead and apply the power
of large-scale, genomic research to many other types of cancer.”
Like most cancers, GBM arises from changes that accumulate in
cells’ DNA over the course of a person’s life — changes that may
eventually lead to the cells’ uncontrolled growth. However, until
recently, scientists have understood little about the precise nature
of these DNA changes and their impact on key biological pathways
that are important to the development of new interventions.
The NCI and the NHGRI initiated TCGA in 2006 to accelerate understanding
of the molecular basis of cancer through the application of current
genome characterization technologies, including large-scale genome
sequencing. TCGA was launched as a pilot program to determine the
feasibility of a full-scale effort to potentially systematically
explore the universe of genomic changes involved in all types of
human cancer.
In its Nature paper, the TCGA Research Network describes
the interim results of its analyses of GBM, the first type of cancer
to be studied in the TCGA pilot. The pioneering work pulled together
and integrated multiple types of data generated by several genome
characterization technologies from investigators at 18 different
participating institutions and organizations. The data include
small changes in DNA sequence, known as genetic mutations; larger-scale
changes in chromosomes, known as copy number variations and chromosomal
translocations; the levels of protein-coding RNA being produced
by genes, known as gene expression; patterns of how certain molecules,
such as methyl groups, interact with DNA, known as epigenomics;
and information related to patients’ clinical treatment.
”This type of comprehensive, coordinated analysis of unprecedented
multi-dimensional data is made possible by advanced technologies
utilized by teams of scientists driven to solve complex questions,"said
NCI Director John E. Niederhuber, M.D. "It will now fall to
a dedicated cadre of laboratory scientists to turn this important
information into new life-saving therapies and diagnostics for
cancer.
TCGA researchers sequenced 601 genes in GBM samples and matched
control tissue, uncovering three significant genetic mutations
not previously reported to be common in GBM. The affected genes
were: NF1, a gene previously identified as the cause of
neurofibromatosis 1, a rare, inherited disorder characterized by
uncontrolled tissue growth along nerves; ERBB2, a gene
that is well-known for its involvement in breast cancer; and PIK3R1,
a gene that influences activity of an enzyme called PI3 kinase
that is deregulated in many cancers. PI3 kinase already
is a major target for therapeutic development. The discovery of
frequent mutations in the PIK3R1 gene means that GBM patients’ responses
to PI3 kinase inhibitors may be dictated by whether or
not their tumors have mutated versions of the gene.
The TCGA team combined sequencing data with other types of genome
characterization information, such as gene expression and DNA methylation
patterns, to generate an unprecedented overview that delineated
core biological pathways potentially involved in GBM. The three
pathways, each of which was found to be disrupted in more than
three-quarters of GBM tumors, were: the CDK/cyclin/CDK inhibitor/RB
pathway, which is involved in the regulation of cell division;
the p53 pathway, which is involved in response to DNA damage and
cell death; and the RTK/RAS/PI3K pathway, which is involved
in the regulation of growth factor signals.
The pathway mapping promises to be particularly informative for
researchers working to develop therapeutic strategies that are
aimed more precisely at specific cancers or that are better tailored
to each patient’s particular subtype of tumor.
For example, a patient whose tumor has genetic alterations at
one point in the CDK pathway might benefit from a drug that blocks
CDK, while patients with mutations at another point in the same
pathway might be predicted not to respond to such drugs. Similarly,
while some drugs already used for GBM target the RTK pathway, the
new findings suggest a need to tailor therapeutic cocktails to
particular patterns of mutations in genes involved in that pathway.
The three pathways were interconnected and coordinately deregulated
in most of the GBM tumors analyzed. Therefore, combination therapies
directed against all three pathways may offer an effective strategy,
the TCGA researchers state.
One particularly exciting finding with the potential for rapid
clinical impact centers on the MGMT gene. Physicians already
know patients with GBM tumors that have an inactivated, or methylated, MGMT gene
respond better to temozolomide, an alkylating chemotherapy drug
commonly used to treat GBM. By integrating methylation and sequencing
data with clinical information about sample donors, TCGA’s multi-dimensional
analysis found that in patients with MGMT methylation,
alkylating therapy may lead to mutations in genes that are essential
for DNA repair, commonly known as mismatch repair genes. Such mutations
then lead to the subsequent emergence of recurrent tumors that
contain an unusually high number of DNA mutations, and that may
be resistant to chemotherapy treatment. If follow-up studies confirm
such a mechanism, researchers say first- or second-line treatments
for such GBM patients may involve therapies designed to target
the results of combined loss of MGMT and mismatch-repair
deficiency. The new findings also may help clinical researchers
figure out the best ways to combine alkylating chemotherapy drugs
with the next generation of targeted therapeutics.
"This represents another major step towards our ultimate
goal of using information about the human genome to improve human
health,"said NHGRI Acting Director Alan E. Guttmacher, M.D. "It’s
thrilling to see what the cancer and genomics research communities
can achieve through working together in a collaborative manner.
I am confident that this paper is just the first of many exciting
results that TCGA will generate."
NCI’s Deputy Director Anna D. Barker, Ph.D., who co-leads the
research program, said, "TCGA’s unprecedented multi-dimensional
data on large numbers of high quality tumor and control samples
offer new molecular insights that will most certainly inform the
discovery of new cancer interventions."
As in the Human Genome Project, TCGA data are being made rapidly
available to the research community through a database, http://cancergenome.nih.gov/dataportal.
The database provides access to public datasets, and with required
review and approval, allows researchers access to more in-depth
data.
The TCGA Research Network members who chaired the large TCGA committee
that wrote the Nature paper were Lynda Chin, M.D., and
Matthew Meyerson, M.D., Ph.D., of Dana-Farber Cancer Institute
and Harvard Medical School, Boston. Dr. Meyerson is also affiliated
with the Broad Institute of MIT and Harvard, Cambridge, Mass.
For a full list of participants in the TCGA Research Network,
go to http://cancergenome.nih.gov/components/index.asp
NCI and NHGRI are two of the 27 institutes and centers at NIH,
an agency of the U.S. Department of Health and Human Services.
For more details about The Cancer Genome Atlas, including Q&As,
a graphic, a glossary, a brief guide to genomics and a media library
of available images, please go to http://cancergenome.nih.gov.
For more information about cancer and the National Cancer Institute,
please visit the NCI Web site at http://www.cancer.gov, or call
NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Additional information about NHGRI can be found at its Web site, http://www.genome.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov. |