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Consortium Members Present Preliminary Results from Multiple Myeloma Genomic Effort

By Andrea Anderson

WASHINGTON, DC (GenomeWeb News) – Researchers from the Broad Institute, the Translational Genomics Research Institute, and elsewhere have garnered genomic data on dozens of multiple myeloma tumors.

Todd Golub, director of the Broad Institute's cancer research program, presented preliminary results from the study at the American Association for Cancer Research annual meeting here this week during a session on "Understanding the Cancer Genome with Next Generation DNA Sequencing." During the session, Golub described efforts to sequence whole genomes or exomes from 38 multiple myeloma patients.

The multiple myeloma genomics project is being funded by the Multiple Myeloma Research Foundation, which is also contributing patient samples from its tissue bank. Broad Institute computational biologist Gaddy Getz is spearheading sequencing for the project, Golub noted. Among other investigators collaborating on the project are TGen President and Scientific Director Jeff Trent, John Carpten, who is director of TGen's integrated cancer genomics division, and Jonathan Keats at the Mayo Clinic.

Multiple myeloma is a cancer of plasma cells in the bone marrow that can lead to bone marrow failure and immune, kidney, and bone problems. The disease, which is relatively rare in the general population but more common in African American populations, has a five-year survival rate of around 30 percent.

In an effort to better understand the disease, members of the Multiple Myeloma Research Consortium Genomics Initiative generated an average of 32 times coverage of 23 whole genomes and an average of 105 times coverage of 16 whole exomes, representing some 93 percent of coding sequences. One individual was sequenced by both whole-genome and whole-exome methods, Golub explained. Peripheral blood samples were used as matched controls for the patients.

On average, the researchers detected an average of 30 non-silent point mutations per tumor, Golub said. Of the 92 mutations selected for validation for genotyping, 87 mutations were subsequently validated by genotyping, suggesting the data being generated is highly accurate and has a low false positive rate.

In an effort to narrow in on the mutations that are most likely to be important, the team used two approaches: one based on the statistical significance of the mutations detected and another based on their prior biological understanding of which mutations appear to have functional consequences.

For instance, Golub said, the team's statistical analysis turned up a dozen genes that are mutated in multiple myeloma, including four previously implicated in the disease. Their analysis of biologically significant mutations, meanwhile, identified a gene that is mutated in at least four patients, along with several other intriguing genes.

From there, the team focused in on biological process and pathways that are altered in multiple myeloma tumors, Golub noted, identifying mutations affecting histone methyltransferases, genes involved in protein translation and blood coagulation pathways, and more.

"These results suggest that sequencing of the multiple myeloma genome will provide new insights into the pathogenesis of multiple myeloma," Golub wrote in the abstract for his AACR presentation, "and moreover suggest that while mutations in particular genes may be rare, they may result in the aberrant activity of common pathways."

In another AACR presentation given during a session on taking biomarkers into clinical practice, TGen researcher Angela Baker discussed some of the data coming out of the team's somatic copy number analyses of multiple myeloma.

That arm of the project involved the use of array-based comparative genomic hybridization and gene-expression profiling to assess multiple myeloma tumors. The team also compared the frequency of specific copy number changes in more than a dozen African American individuals and nearly 200 Caucasian individuals.

Results from that work so far suggest African American individuals with multiple myeloma are more likely to have tumors containing specific chromosome 1 deletions that have been linked to poor multiple myeloma outcomes.

"[T]hese results suggest that biological differences in the manifestation or progression of the disease should not be ruled out," Carpten said in a statement. "The high-resolution data generated through the MMRC Genomics Initiative now enables us to uncover new clues about the genetic determinants of multiple myeloma in patients with more aggressive disease."