March 24, 2011

New Clues Revealed For Multiple Myeloma

Scientists reported on Wednesday that they have sequenced the entire genetic code of 38 multiple myeloma patients, and have uncovered the most likely genetic causes of the aggressive blood cancer.

The work, carried out by 21 institutions in the U.S. and Canada, offers the most comprehensive picture to date of the full genetic blueprint of multiple myeloma, and provides new and unexpected insights into the events that lead to the disease.

"For the first time, we are able to see on a molecular basis what might be causing this malignancy," said study author Dr. David Siegel at the John Theurer Cancer Center at Hackensack University Medical Center.

"We already know what causes many types of cancer, but until now we had few clues to the causes of myeloma."

The sequencing revealed genes never before associated with cancer, as well as multiple genetic mutations that disrupt 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 examined such a large collection of samples.

"Already, we can see that mutations are funneling into a limited number of pathways," said co-senior authors Todd Golub at the Broad Institute of Harvard University and the Massachusetts Institute of Technology and Charles Dana at the Dana-Farber Cancer Institute.

Multiple myeloma is the second most common blood cancer in the United States, with roughly 20,000 new cases diagnosed each year.

The disease begins in the bone marrow, where plasma cells (a type of white blood cell) become malignant, attacking solid bone and crowding out normal cells that help the immune system.   The disease can develop in people with no known risk factors or family history, and typically leaves its victims susceptible to infections and other serious complications.  The five-year survival rate is less than 40 percent.

Scientists have never before taken such an in-depth look at so many multiple myeloma samples. 

"This is a demonstration of the value of looking at more than just a single tumor at great depth," said Dr. Siegel.

Genomic sequencing involves looking through the DNA code for tiny variations that could explain why some people are at risk of disease while others are not.

The cost of sequencing has dropped dramatically in recent years, allowing researchers to cast their net wider than ever.  Using the latest machines from Illumina Inc. and Life Technologies Corp., for instance, means scientists can map out a patient's entire DNA code in just a few weeks for as little as $5,000, compared with the 13 years and $3 billion it took to sequence the first human genome ten years ago.

Meanwhile, "next-generation" technologies that can sequence DNA at a rapid pace and deliver massive amounts of data in a short period of time have surged in recent years.  This has allowed scientists to sequence the DNA of many different multiple myeloma patients, whereas previous studies into multiple myeloma have only been able to examine the DNA of a single patient.

Nevertheless, 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.

In the current research, scientists studied 38 multiple myeloma patients, comparing the patients' normal genomes to the genomes from their malignant cells.

"If we compare the tumor genome to the normal genome, that gives us great clues about what makes a normal cell into a cancer cell," Golub said.

A preliminary analysis of the DNA variations suggests there are common pathways, particularly in the cellular protein-making machine, that enable a malignant cell to survive, invade and spread.

Golub said the sequencing revealed many new avenues for future multiple myeloma treatments, including several genes that have never before been implicated in any cancer.

"We have a number of examples of genes that were not thought to play a role, but they must be important," he told Reuters.

"It sends the field in a new direction that they couldn't have anticipated before."

However, "it's going to take a lot of biological research to sort out whether these will make good drug targets," he added.

"But this is an example of how genetic analysis can help point the field in the right direction very dramatically."

The initial results suggest that about 4 percent of patients with multiple myeloma have mutations in the BRAF gene, the same type of mutations found in some melanoma patients.

So far, melanoma patients with this particular mutation have shown a strong response to an experimental drug under development by Roche and Plexxikon.  The researchers hope the drug, or others like, might also help a small subset of multiple myeloma patients.

"An important next phase will be to explore that hypothesis in a clinical trial," Golub said.

Another key finding, borne out by mutations in 11 patients, was a broader than anticipated role for NF-Kappa Beta signaling in myeloma. NF-Kappa Beta is a protein that regulates cell division and cell death (apoptosis). Earlier research had found that NF-Kappa Beta was over-expressed in multiple myeloma.

"Our study confirms this pathway in myeloma, and points to potential directions for myeloma treatment," said Dr. Siegel.

"This is a major finding in that it will provide a roadmap of where to attack this disease and to understand the different species of the disease."

Golub said the study highlights the power of new gene-sequencing technology that allows researchers to look at the whole genetic makeup of a cancer, something that was not possible even five years ago.

"This has been made possible not by our brilliance but by advances in new gene sequencing technology," he said, adding that the study represents a new approach in cancer research.

"It is a very positive development that will enable the field to see things that were previously not imaginable," he said.

"Five years from now, we will have the genetic landscape of all common human cancers mapped out."

The findings were published in the March 24 edition of the journal Nature.  


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