Sequencing and analysis of nearly 40 tumor genomes points multiple myeloma research in new directions
Todd Golub, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber Cancer Institute
Scientists have unveiled the most comprehensive picture to date of
the full genetic blueprint of multiple myeloma, a form of blood cancer. A
study of the genomes from 38 cancer samples has yielded new and
unexpected insights into the events that lead to this form of cancer and
could influence the direction of multiple myeloma research.
This work, led by scientists at the Broad Institute and Dana-Farber Cancer Institute, appears in the March 24 issue of Nature.
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, MD,
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
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
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-κB 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
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
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 www.broadinstitute.org.
Broad Institute of MIT and Harvard
Dana-Farber Cancer Institute