Sequencing and analysis of nearly 40 tumor genomes points
multiple myeloma research in new directions
PHOENIX, Ariz. - March 23, 2011 - A nationwide study by 20
institutes, including TGen, has unveiled the most comprehensive
picture to date of the genetic blueprint of multiple myeloma, an
all-too-common form of bone marrow cancer.
"This is arguably the largest cancer genome discovery study done to
date," said Dr. John Carpten, Director of the Integrated Cancer
Genomics Division at the Phoenix-based Translational Genomics
Research Institute (TGen), a key member of the national Multiple
Myeloma Research Consortium, and a co-author of the research paper
that will appear in the March 24 issue of the prestigious journal
Nature.
The study, led by scientists at the Broad Institute and Dana-Farber
Cancer Institute, involved whole genome sequencing of normal and
tumor DNA from 38 multiple myeloma patients to assess
tumor-specific changes across the entire 3-billion-letter human
genome, yielding new and unexpected insights into the events that
lead to this form of cancer.
But first, TGen provided an initial analysis of 250 multiple
myeloma tumor samples. Using gene expression profiling microarrays
and genome copy number arrays - powerful high-throughput
investigative technologies that can assess the state of the vast
majority of human genes - TGen scientists identified numerous
overly active genes that likely play a role in multiple
myeloma.
"Our data was used to identify several of the gene sets that became
the targets in the study investigated with our collaborators," said
Dr. Angela Baker, a staff molecular biologist in Dr. Carpten's lab
and a co-author of the scientific paper in Nature.
Dr. Jeffrey Trent, TGen's President and Research Director, and also
a co-author of the paper, said this pioneering study will have a
major impact in the field of multiple myeloma, and will influence
research into other forms of cancer, too.
"This study sets the stage for ever-more-precise and detailed
investigations that should eventually pinpoint the genetic and
genomic origins of this devastating disease," Dr. Trent said. "The
next stage will be to look at how these genes affect cellular
growth and proliferation that can lead to cancer."
Multiple myeloma is the second most common blood cancer in the
United States and causes about 20,000 new cases in this country
every year. The disease's five-year survival rate is less than 40
percent, which is low compared to other forms of cancer. Multiple
myeloma begins in the bone marrow, where plasma cells (a type of
white blood cell) become malignant, crowding out normal cells and
attacking solid bone. No one knows the cause of the disease - it
can develop in people with no known risk factors and in many cases,
no family history of multiple myeloma.
The emerging genome-wide picture of multiple myeloma reveals genes
never before associated with cancer as well as multiple genetic
mutations that disrupt just a handful of common pathways, or chains
of chemical reactions that trigger a change in a cell.
Individually, each of these mutations is fairly uncommon and might
have remained undiscovered had the researchers not looked at such a
large collection of samples.
"Already, we can see that mutations are funneling into a limited
number of pathways," said co-senior author Todd Golub, director of
the Broad's Cancer Program and Charles A. Dana Investigator in
Human Cancer Genetics at the Dana-Farber Cancer Institute. "This is
a demonstration of the value of looking at more than just a single
tumor at great depth."
Never before have scientists taken an in-depth look at so many
multiple myeloma samples. Over the last six years,
"next-generation" sequencing technologies - machines that can
sequence DNA at a rapid pace and deliver massive amounts of data in
a short period of time - have surged. Sequencing the full genome of
a tumor is still a feat of technical and analytical prowess and
only a few studies to date have looked across more than one. The
team of researchers studied 38 multiple myeloma patients, comparing
the patients' normal genomes to the genomes from their malignant
cells.
With the whole cancer genome in view, one of the most challenging
aspects of multiple myeloma research is now separating so called
driving events - the important mistakes that drive cells toward
becoming cancerous - from passenger mutations, genetic alterations
that are merely along for the ride. A team of researchers led by
co-senior author Gad Getz, director of Cancer Genome Analysis at
the Broad Institute, has developed computational tools to address
this.
"Next-generation sequencing has the great potential and promise to
allow us to comprehensively analyze the cancer genome at extremely
high resolution and see all of the events that happen in cancer,"
said Getz. "These tools that we've developed are state-of-the-art.
We've been able to dramatically decrease the error rate for
detecting all types of mutations. Now, we can find those genes
whose mutations occur more than expected by chance."
The researchers found sets of mutations affecting many genes in the
same pathways, including the NF-kB pathway. If this pathway is
turned on at the wrong time, it can activate genes that allow a
cancer cell to grow and divide unchecked. Previously, multiple
myeloma researchers had suspected that this pathway was involved in
the cancer's development, but it was unclear exactly what events
were turning this pathway on. In this latest study, the researchers
discovered 11 different genes involved in this pathway that were
altered in at least one multiple myeloma sample.
Additionally, the study has brought to light new mutations
affecting genes that had never previously been tied to cancer.
"These genes, which are frequently mutated, were not on anyone's
radar before when thinking about multiple myeloma specifically or
cancer in general," said Golub, who is also an investigator at
Howard Hughes Medical Institute, and professor of pediatrics at
Harvard Medical School. "This shows that there are entirely new
cancer-causing genes that are going to be discovered through these
sequencing efforts."
In half of the study's patients, the researchers found mutations in
genes that control two fundamental cellular processes: how RNA is
processed and proteins are folded. Two of these genes, DIS3 and
FAM46C, appear to play important roles in the stability of RNA and
hence its translation into protein. Researchers also found genes
involved in blood clotting mutated in multiple myeloma patients, a
new and surprising discovery. Follow-up studies will be needed to
understand what role these defective genes play in cancer and how
they can inform treatment.
"It's going to take a lot of biological research to sort out
whether these will make good drug targets," said Golub, "but this
is an example of how genetic analysis can help point the field in
the right direction very dramatically."
One finding with more immediate clinical importance is the
discovery of BRAF mutations in a small number of multiple myeloma
patients. BRAF mutations have "never been a part of the multiple
myeloma lexicon before," according to Golub, but have been
previously seen in other forms of cancer, including melanoma and
colon cancer. Drugs are now in clinical development to target this
particular gene and have shown promising early results in patients
with melanoma.
When the scientists looked at samples from over 150 patients with
multiple myeloma, they found BRAF mutations in about four percent
of cases. Further studies will be needed to see if drugs that
inhibit BRAF are as effective in patients with multiple myeloma as
they have been in patients with melanoma.
Golub pointed out that with more samples and the analytical tools
to look genome-wide, a new picture of the multiple myeloma genome
is beginning to develop, and with it, new genetic insights. "This
study shows that there really are entirely new cancer-causing genes
that are going to be discovered through these efforts," he
said.
All of the data generated through this project have been made
publicly available to cancer researchers worldwide. Funding for
this project was provided by the Multiple Myeloma Research
Foundation and tissue samples were provided by the Multiple Myeloma
Research Consortium tissue bank.
# # #
Paper cited:
Chapman MA et al. Initial genome sequencing and analysis of
multiple myeloma. Nature. March 24, 2011. DOI:
10.1038/nature09965
*
About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was
launched in 2004 to empower this generation of creative scientists
to transform medicine. The Broad Institute seeks to describe all
the molecular components of life and their connections; discover
the molecular basis of major human diseases; develop effective new
approaches to diagnostics and therapeutics; and disseminate
discoveries, tools, methods and data openly to the entire
scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the
visionary Los Angeles philanthropists Eli and Edythe L. Broad, the
Broad Institute includes faculty, professional staff and students
from throughout the MIT and Harvard biomedical research communities
and beyond, with collaborations spanning over a hundred private and
public institutions in more than 40 countries worldwide. For
further information about the Broad Institute, go to
http://www.broadinstitute.org.
For more information, contact:
Broad Institute of MIT and Harvard
Nicole Davis
617.714.7152
[email protected]
*
About Dana-Farber Cancer Institute
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
Cancer Institute. It provides adult cancer care with Brigham and
Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center
and it provides pediatric care with Children's Hospital Boston as
Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the
top ranked cancer center in New England, according to U.S. News
& World Report, and one of the largest recipients among
independent hospitals of National Cancer Institute and National
Institutes of Health grant funding.
For more information, contact:
Dana-Farber Cancer Institute
Bill Schaller
617-632-5357
[email protected]
*
About TGen
The Translational Genomics Research Institute (TGen) is a Phoenix,
Arizona-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. Research at
TGen is focused on helping patients with diseases such as cancer,
neurological disorders and diabetes. TGen is on the cutting edge of
translational research where investigators are able to unravel the
genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen
believes it can make a substantial contribution to the efficiency
and effectiveness of the translational process. TGen is affiliated
with the Van Andel Research Institute in Grand Rapids, Michigan.
For more information, visit: www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]