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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.

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Credit: Wikipedia Commons

Tagged: Biomedicine, cancer, DNA, genome, sequencing, myeloma, Broad Institute

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