A Closer Look
Genome Study of Multiple Myeloma Opens New Avenues for Research
In the most comprehensive genetic analysis of multiple myeloma to date, researchers have sequenced the genes of 38 patients with this uncommon blood cancer. The study confirmed some of the mutations known to play a role in this disease and uncovered additional alterations in genes and pathways that can now be investigated further.
For 23 of the patients, Dr. Michael Chapman of the Broad Institute and his colleagues sequenced the entire genomes of tumor cells and matched normal cells. A comparison of the results revealed suspicious changes in parts of the genome where no one had thought to look before, the researchers reported in the March 24 Nature.
“Our hope is that this study will catalyze research in [the field of] multiple myeloma,” said Dr. Todd Golub of the Broad Institute and a leader of the study. Just a few years ago, the idea of decoding the genes of 38 patients with myeloma would have been unimaginable, he noted. But the recent introduction of new and cheaper technologies for sequencing DNA has made the goal achievable.
“We still see this as a preliminary study, but we can now launch into the next phase of the research with a higher level of confidence that the effort will bear fruit,” said Dr. Golub, who directs Broad’s cancer program. He presented initial results from the study last year.
The project was spearheaded by the Multiple Myeloma Research Foundation (MMRF), which was created in 1998 to speed the development of new treatments. The causes of this disease are unknown, and there is no cure. Multiple myeloma affects plasma cells, which are a type of white blood cell. Approximately 20,000 people are diagnosed with the disease in the United States each year, and the 5-year survival rate is less than 40 percent, the researchers noted.
An Unexpected Finding with Clinical Implications
A finding of particular interest was the discovery that some patients in the study had mutations in the BRAF gene, which is frequently mutated in melanoma and can drive cell growth. A number of BRAF inhibitors are in development, including PLX4032, which has shown promise in early trials in patients with melanoma.
Although the finding of BRAF mutations in myeloma was unexpected, the discovery raised the possibility that an existing drug could benefit some patients with the disease, noted co-author Dr. Kenneth Anderson of the Dana-Farber Cancer Institute. This finding, he added, underscores the importance of patients participating in clinical trials to evaluate potential therapies.
“I’ve been treating patients with multiple myeloma for over 30 years, and there’s never been a more exciting time to make science work for patients,” said Dr. Anderson. Genetic approaches, he continued, should allow researchers to identify the specific alterations in a patient’s disease and use the information to select potential therapies and develop new ones. “One can advance the idea of picking the right medicine for the right patient at the right time,” he added.
While the discovery of BRAF mutations may point to potential treatments, the genome study also yielded clues to the underlying biology of the disease.
Mutations were found in genes involved in RNA processing and protein folding, processes that are important for how normal cells function. Half of the patients had defects in one or more of these genes, including one called FAM46C that had never been linked to cancer before.
“We feel like we know so much more about this disease and about where our investigators should go in the future,” said Kathy Giusti, the founder and chief executive officer of MMRF. A former pharmaceutical company executive who was diagnosed with multiple myeloma at age 37, she has been treated with the best therapies available.
When Giusti and her colleagues began to plan the genome study in 2005, they knew that high-quality specimens would be critical to the project’s success. The MMRF had launched a tissue bank the previous year, and the 38 samples selected for the genome study came from this bank.
Collecting the appropriate samples “is one of the most challenging elements in conducting genomics research,” Giusti said. But the MMRF has been successful. Since 2005, more than 3,000 patients have voluntarily donated bone marrow, blood samples, and related medical information to the tissue bank, according to the group.
Though not reported in the Nature study, samples from 250 additional patients have been profiled for genetic changes such as gains and losses of DNA at the Translational Genomics Research Institute (TGen). If the costs of sequencing DNA continue to drop, many or all of these samples may eventually be sequenced, Dr. Golub said.
More myeloma genomes need to be analyzed to develop a more complete picture of the genetic landscape of the disease, the researchers said. By focusing on a collection of patients rather than just a few individuals in the current study, the researchers uncovered mutations in 11 genes in the NF-kappa B signaling pathway, which promotes the growth of cancer cells.
Mutations were also found in genes that play a role in the packaging of DNA, or chromatin remodeling. Alterations of this type may affect the regulation of genes elsewhere in the genome and have been found in several cancers recently, including in a rare form of pancreatic cancer, a type of lymphoma, and the childhood cancer medulloblastoma.
Mutations in chromatin remodeling genes are increasingly becoming recognized in cancer, but “the field is very young and we do not yet understand the exact biological consequences of these changes,” said Dr. Golub.
Making the Information Available
Looking ahead, Dr. Golub cautioned that it will be a challenge to translate the findings from genome studies into the clinic, in part because multiple genes play a role in myeloma. “It won’t be a matter of just testing a patient for one or two genes,” he said.
To accelerate progress against the disease, data from this initiative and other efforts are available to the scientific community through the Multiple Myeloma Genomics Portal.“These results are exciting,” Dr. Golub said, “because they provide a glimpse of what is coming in cancer genomics.” A few days ago, another group of researchers announced that they had sequenced the tumor and normal genomes of 50 patients with a type of breast cancer.
While these are the largest cancer genome studies reported to date, they will likely be eclipsed by even larger studies in the months and years ahead.
Further reading: Why are Tissue Samples Important to Cancer Genomics?