By Monica Heger
This story was originally published on March 24.
A consortium of researchers including scientists from the Broad Institute and the Dana-Farber Cancer Institute reported yesterday that the sequencing of tumor samples from 38 multiple myeloma patients could have both immediate and future clinical impact.
The Multiple Myeloma Research Consortium Genomics Initiative, funded by the Multiple Myeloma Research Foundation, completed the sequencing last year, and presented preliminary results at last year's American Association for Cancer Research meeting (IS 4/27/2010). This week, the researchers reported the full results in Nature.
The team studied 38 multiple myeloma patients by sequencing the whole genomes of 23 patients and the whole exomes of 16 patients on the Illumina Genome Analyzer, and identified novel mutations of unknown significance, known mutations, and a mutation known to be present in melanoma and for which there are currently drugs on the market.
"Very excitingly, it may be possible to use available drugs on the shelf that are effective in melanoma to treat myeloma patients with similar mutations," Kenneth Anderson, the program director and chief of hematologic neoplasias at the Dana-Farber Cancer Institute, told Clinical Sequencing News, adding that while the results need to first be validated, he envisions a "rapid bench-to-bedside translation."
Todd Golub, a lead author of the paper and director of the cancer program at the Broad Institute, said in a telebriefing about the study that while the work is preliminary, and the results still need to be confirmed and more genomes sequenced, it "will have future ramifications for therapies" and provides additional evidence and confidence that the use of sequencing to identify therapeutic targets in cancer "will bear fruit."
The team identified 10 protein-coding genes that were frequently mutated including three previously reported genes: KRAS, NRAS, and TP53. Additionally, they identified two point mutations in CCND1, which has been recognized as a target of chromosomal translocation in multiple myeloma, but for which mutations had not been previously observed. The remaining six genes were novel findings and "indicate new aspects of pathogenesis of multiple myeloma," the authors wrote.
Golub said the findings could be categorized into three areas of clinical importance. First, the study helped clarify genes and pathways previously suspected to be important in the pathogenesis of multiple myeloma. Second, it identified genes that "weren't on anyone's radar for multiple myeloma or any cancer." Finally, it identified a mutation in the BRAF oncogene, which is known to be mutated in melanoma, and for which there are currently drugs available that have been shown to be effective in melanoma patients with BRAF mutations.
The finding that could have the most immediate impact is the mutation in the BRAF gene. While only one sequenced patient harbored that mutation, the researchers focused on it because of its known clinical relevance. The mutation they found is known to be oncogenic. The gene is also known to be mutated in melanoma, and there are currently drugs on the market that target it. The team genotyped an additional 161 multiple myeloma patients for the 12 most common BRAF mutations, and found mutations in seven patients.
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"This does not prove that these patients will respond [to BRAF inhibitors]," said Golub, but "it provides the groundwork … to test them in a clinical trial as rapidly as possible."
While this mutation is the most immediately actionable, the sequencing also revealed mutations in genes involved in RNA processing, protein translation, and protein homeostasis. These pathways have previously been implicated in multiple myeloma, and the finding of additional genes expands the possible range of therapeutic targets.
According to Anderson, one of the hallmark characteristics of multiple myeloma is the overproduction of protein, and drugs that inhibit proteasomes — protein complexes that degrade unneeded or damaged proteins — have been found to be effective therapies for multiple myeloma. The finding of additional genes in the same pathway could lead to "opportunities in targeting protein homeostasis more broadly than the proteasome," he said.
The team identified mutations that affect protein translation and homeostasis in 42 percent of the patients.
For example, the team identified mutations of the DIS3 gene in four out of 38 patients and mutations in LRRK2 in three out of 38 patients. The DIS3 gene is involved in RNA regulation, while the LRRK2 gene is involved in translation initiation and plays a role in the predisposition to Parkinson's disease.
Mutations to genes that have never before been studied were also found, including in the FAM46C gene, a finding made possible with the use of sequencing technology. Mutations in this gene were found in five out of 38 patients. Golub said a PubMed search of the gene turned up zero papers.
When the team examined its expression in 414 multiple myeloma samples and compared it to expression in 395 gene sets in the Molecular Signatures Database, they found "strong evidence that FAM46C is functionally related in some way to the regulation of translation," the authors wrote.
While the sequencing revealed important insights into the pathways involved in multiple myeloma and even suggested that an existing drug may be effective, studies like this one require enormous resources, Kathy Giusti, a cofounder of the MMRF, said on the conference call, including access to samples and adequate funding.
Giusti said the MMRF invested $12 million in the study. The foundation also collected around 1,800 samples, of which about 250 were used in the study, including the 38 that were sequenced. All 250 were also analyzed by researchers at the Translational Genomics Research Institute for copy number variants and gene expression, important steps toward interpreting the sequence data.
"Access to tissue is one of the most challenging elements to be able to conduct genomic studies," Giusti said.
However, she said, the results from the study have encouraged the foundation to invest in two biotech companies — Epizyme and Constellation Pharma — to support drug development. It will also be launching a multi-million dollar personalized medicine project by the end of the year involving 1,000 patients. The project will collect bone marrow from patients at the time of diagnosis and at various time points throughout progression for further analysis, possibly including sequencing.
Additionally, the consortium plans to further study the results of this study, including potentially sequencing all 250 multiple myeloma patient samples.
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