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A study led by researchers at Dana-Farber Cancer Institute and Broad
Institute of the Massachusetts Institute of Technology and Harvard
University provides the first demonstration of a practical method of
screening tumors for cancer-related gene abnormalities that might be
treated with "targeted" drugs.
The findings, published online today on the Nature Genetics Web site, may help relieve a bottleneck between scientists' expanding
knowledge of the genetic mutations associated with cancer and the still
nascent ability of doctors to use that knowledge to benefit patients.
The results constitute an important step toward the era of "personalized
medicine," in which cancer therapy will be guided by the particular set
of genetic mutations within each patient's tumor, the authors suggest.
"It's universally recognized that cancer is a disease of the genome,
of mutations within genes responsible for cell growth and survival, and a
great deal of effort has gone into finding those mutations, to the
point where several hundred to a thousand are now known," said the
study's senior author, Levi Garraway, MD, PhD, of Dana-Farber and the
Broad Institute. "The challenge has been how to determine which of them
are involved in each of the hundreds of kinds of cancer that occur in
humans — and to develop accurate, affordable methods of detecting key
mutations in tumor samples. This study suggests that such a method is
feasible on a large scale."
The authors took advantage of a scientific serendipity to devise a
simple test to detect important cancer mutations. Mutations in oncogenes
(genes linked to cancer) do not occur randomly; rather, they seem to
arise most frequently in certain regions of the oncogenes. As a result,
researchers didn't necessarily have to scan the entire length of each
gene, but could focus instead on the sections most likely to harbor
They performed these screenings with a technology known as
high-throughput genotyping, a fast, relatively inexpensive way of
profiling gene mutations within cells. It involves extracting DNA from a
tumor sample, copying this material thousands of times, depositing
segments of it in tiny "wells" on a small plate, and mixing in reagents
that reveal whether each segment carries a specific mutation. Automated
equipment then reads the plates to determine which mutations are present
in each sample.
In the study, the researchers scanned 1,000 human tumor samples for
238 known mutations in 17 specific oncogenes. (Those 17 were chosen
because they are mostly "classic, well-known" contributors to cancer,
Garraway stated.) They found at least one mutation in 298 of the
samples, or 30 percent of the entire group, which was in keeping with
the rates reported in scientific literature for the types of cancer
"Mutations were identified in the percentages we expected," Garraway
said, "which indicates this technique is on-target for the mutations we
were interested in. Overall, the technique worked very well: we were
able to obtain mutation profiles that were accurate, sensitive, and
cost-effective." The cost of processing each sample was between $50 and
$100, although the figure would probably be somewhat higher if the
technology were used in cancer clinics to test for large numbers of
The scans produced some surprises as well. Mutations were found in
several types of tumors where they had not been previously recognized.
Researchers also discovered an unexpectedly large number of instances
where the same set of mutations co-occurred within tumor cells,
suggesting that oncogenes often work in partnership.
As promising as high-throughput genotyping is for cancer treatment
and research, its capacity will need to be expanded so it can handle
larger numbers of mutations. The next step, Garraway explained, would be
to work with clinical investigators to explore whether use of the
technology is feasible in a clinical setting and whether it actually
improves doctors ability to classify and treat individual tumors.
"We've shown the practical potential of this technique," observed
Garraway, who is also an instructor in medicine at Harvard Medical
School. "It is a step toward the day when cancer patients will routinely
have their tumors scanned for specific mutations, and treatment will be
based on the cancer's particular genetic profile."
Major funding for the study was provided by grants from Genentech,
Inc., the American Cancer Society, the National Cancer Institute, the
Prostate Cancer Foundation, the Burroughs-Wellcome Fund, the Robert Wood
Johnson Foundation, and the Novartis Institute for Biomedical Research.
The co-lead authors of the paper are Roman Thomas, MD, formerly of
Dana-Farber and the Broad Institute, and Alissa Baker of Dana-Farber,
who contacted cancer researchers around the world to obtain the 1,000
tumor samples used in the study. Co-authors include Matthew Meyerson,
MD, PhD, also of Dana-Farber and the Broad Institute, and researchers
from Dana-Farber; the University of Texas Southwestern Medical Center;
Nagoya City University Medical School, in Nagoya, Japan; the David
Geffen School of Medicine at the University of California at Los
Angeles; Brigham and Women's Hospital; University Hospital of Zurich,
Switzerland; Northwestern University Feinberg School of Medicine; the
National Cancer Institute; National Naval Medical Center; the Medical
University of Vienna, Austria; the Center of Molecular Medicine at the
Austrian Academy of Sciences; the Wistar Institute in Philadelphia; the
Navartis Institutes for Biomedical Research; Harvard Medical School; the
Max-Planck Institute for Neurological Research in Cologne, Germany;
and the University of Cologne.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National