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Consortium Reports on Findings from Multiple Myeloma Genomes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Researchers from the Multiple Myeloma Research Consortium have sequenced dozens of multiple myeloma genomes and exomes, identifying known and previously unappreciated processes and pathways that contribute to the disease.

In a paper appearing in today's issue of Nature, the MMRC team described how it used whole-genome and exome sequencing to assess tumor genomes from 38 individuals with multiple myeloma. In the process, the researchers tracked down recurrent changes in several pathways, including those involved in RNA processing, protein translation, histone methylation, and blood coagulation.

Those involved in the study say the findings provide new clues for characterizing and treating the disease — and highlight the additional information that can be collected by sequencing a collection of tumors rather than a single sample.

"Mutations often do not occur at very high frequency," senior author Todd Golub, director of the Broad Institute's cancer program, said during a telephone briefing with reporters yesterday. "If that's the case, then developing a complete understanding of the broad landscape of a tumor such as multiple myeloma will require sequencing many genomes."

"We still see this as a preliminary study," he added. "We believe that sequencing additional multiple myeloma genomes will be necessary to get the complete picture of the multiple myeloma genome."

Multiple myeloma is a blood cancer that affects mature B-lymphoid plasma cells, a type of white blood cell. Previous research has unearthed several chromosome translocations that contribute to the disease, researchers noted, but there are many more genetic changes still to be detected.

And while survival times have improved somewhat for multiple myeloma patients, co-author Kenneth Anderson, a medical oncologist at the Dana-Farber Cancer Institute, told reporters, individuals with the disease typically relapse with time.

"It remains, at least in most patients, an incurable disease," Anderson said, noting that the new sequencing study "will allow us to more appropriately understand the heterogeneity of multiple myeloma, better segment patients, better identify novel targets, and ultimately, to validate novel, targeted therapies."

To find genetic glitches involved in multiple myeloma, the team sequenced tumor genomes from a group of patients — a Multiple Myeloma Research Foundation-funded effort that Golub described at the American Association for Cancer Research annual meeting last spring.

"Recent reports have described the sequencing of whole genomes from a single patient," the group wrote. "Although informative, we hypothesized that a larger number of cases would permit the identification of biologically relevant patterns that would not otherwise be evident."

Using the Illumina GAII, they did whole-genome sequencing of tumor DNA from bone marrow from 23 individuals with multiple myeloma, along with exome sequencing of tumor samples from 16 other individuals. One individual's tumor was sequenced using both whole-genome and exome sequencing.

Gene expression and copy number information on roughly 250 multiple myeloma samples were used to help interpret the genome and exome data, Golub noted.

When they compared the tumor genomes and exomes to genetic patterns in matched normal blood samples, the team found several recurrent somatic mutations predicted to change protein sequences. These included mutations in TP53, KRAS, NRAS and other known multiple myeloma genes, as well as changes to several genes involved in pathways previously linked to the disease, such as the NF-kappa B pathway.

But the researchers found recurrent mutations in new and unexpected places as well. For instance, about four percent of patients had activating mutations in BRAF — a gene that's previously been linked to the skin cancer melanoma.

Because drugs targeting the BRAF pathway are already being developed for melanoma, they explained, it might be possible to exploit such therapies to treat some individuals with multiple myeloma.

"No one was thinking about BRAF as a potential driver of multiple myeloma or therapeutic target in multiple myeloma," Golub said. "But this multiple myeloma genome sequencing effort … suggests a new hypothesis: that perhaps some myelomas are being driven by the BRAF oncogene.

"If this is the case," he added, "it's a reasonable hypothesis to test to ask whether such tumors might be dependent on BRAF for survival and, therefore, might respond to BRAF inhibitors that were developed for a different reason, for melanoma."

Though research and clinical trials are needed to determine whether that's the case, MMRF Founder and CEO Kathy Giusti noted that that foundation is reaching out to at least one company developing BRAF-targeting compounds.

The sequencing effort also uncovered mutations in genes from contributing to several other key processes, such as RNA processing and protein translation and homeostasis-related pathways.

In addition, the team explained, mutations affecting histone modifying genes — particularly histone methyltransferase enzyme coding genes — point to possible epigenetic alterations in multiple myeloma. That, in turn, hints that it may eventually be possible to come up with epigenetics-related treatments for the disease as well.

Based on these findings, the MMRF has invested $5 million in an epigenetics-related program, Giusti said during the press briefing, funding two biotech companies with a focus on epigenetics. And, she said, the foundation recently held a forum looking at epigenetics-related issues in multiple myeloma and other types of cancer.

The MMRF also plans to launch a personalized medicine initiative later this year that will bring together genomic, clinical, and treatment information for 1,000 individuals with multiple myeloma over several years, Giusti said.

"We feel like we know so much more about our disease and where our future investments must go so we can really move toward a reality in which treatments will be matched to disease profiles and disease segments."

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