The largest cancer genome sequencing project yet highlights molecular pathways at the heart of an aggressive blood cancer.
By comparing the genome sequence of healthy and cancerous cells in 38 people diagnosed with multiple myeloma—an aggressive blood cancer—scientists have created a molecular map of what goes awry in this disease.
The findings, published today in Nature, point to new targets for drug development, and also suggest that some patients will respond to drugs currently being tested for other types of cancers.
The study is also the first published analysis of multiple whole genomes of the same cancer, reflecting continuing advances in sequencing technologies and the ability to analyze whole-genome data.
Thanks to a steady decline in the cost of genome sequencing, scientists have analyzed a growing number of tumors in recent years. Searching for differences between the DNA sequence of patients' healthy and cancerous cells can highlight genetic mutations that may underlie the cancer cells' ability to grow and survive. But most studies have analyzed a single cancer sample in great detail, and then sequenced relevant genes in other cancers to confirm the role of candidate mutations.
"Simply sequencing a tumor genome doesn't get you the information you need," says Todd Golub, director of the cancer program at the Broad Institute and senior author of the study. "We need the ability to look across many cancer genomes and to discover mutations that are recurring at low frequencies, so that we can see patterns emerging from the data that are biologically meaningful."
Scientists already suspected that a protein called NF-Kappa Beta, which regulates cell division and cell death, plays a role in myeloma. In the new study, researchers found mutations in 11 genes that are part of the NF-Kappa Beta pathway that were altered in at least one multiple myeloma sample. "Now we have a detailed blueprint for how those pathways were aberrantly activated in disease," says Golub. "You can only see those kinds of pattern when you look at multiple genomes."
Researchers also found that about 4 percent of patients have mutations in a gene known as BRAF. This finding could be used to help select effective drugs. BRAF mutations have previously been shown to play a major role in melanoma and other cancers, and several BRAF inhibitors are now being tested in melanoma patients, some with excellent results. "It was completely unexpected that myeloma patients might benefit from similar targeted therapies," says Kenneth Anderson, chief of the division of hematologic neoplasias at the Dana Farber Cancer Institute. "Perhaps we can take a drug off the shelf and help patients in the short term." No trials of these drugs in this subset of myeloma patients have yet been launched, but Golub says discussions are underway. The researchers also discovered novel mutations that haven't previously been linked to cancer, pointing to new avenues for research. "No one studying myeloma had even heard of these genes," says Golub. "We don't know what these mutations do or how they cause cancer, or even whether they will make good drug targets, but it tells you this is where the field should be looking in greater detail."
The project was the brainchild of the Multiple Myeloma Research Foundation, a patient advocacy group that funded the research and provided cancer samples. About 20,000 new cases of multiple myeloma are diagnosed in the U.S. each year. The disease has a five-year survival rate of less than 40 percent. Kathy Giusti, the organization's founder, says the findings are already being used to direct funding decisions. The study identified mutations in enzymes involved in the way DNA is packaged, so the foundation has invested $5 million in this area of research and funded two biotech companies working in the field.
Scientists are now sequencing additional myeloma genomes and expect to have a few hundred completed in the next two years. "The field is barreling forward such that we expect many thousands of genomes to be sequenced across different cancer types in next several years," says Golub.
The next step is to figure out what role these mutations play in cancer. "Do they activate or inactivate growth and survival, drug resistance, or signaling pathways?" says Anderson. To do this, scientists study the effect of the mutations in cancer cell lines and animal models of the disease. "That will open the potential for development of novel targeted therapeutics directed at fundamental genetic abnormalities that are hallmarks of this disease," says Anderson.