Multiple Myeloma Data Analysis Shows Need For Diversity In Research
By Allison Proffitt
November 22, 2017 | An analysis of data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study by researchers from the Keck School of Medicine of the University of Southern California (USC) Department of Translational Genomics found significant genetic mutation differences between African Americans and Caucasians with multiple myeloma. African American patients showed increased mutations in genes previously unassociated with multiple myeloma. The findings were published today in PLoS Genetics.
The ten-year CoMMpass study is as close to a “pure” study as you can get, Zarko Manojlovic, Assistant Professor of Research at USC in the Department of Translational Genomics and lead author of the paper, told Bio-IT World. All of the patients were treatment-naïve, all had access to the same cancer treatment, and the sequencing was all done in the same facility. “There was a lot of consistency,” Manojlovic said. “That sort of helped… to find some of these mutations which could have possibly been lost under the noise.”
Manojlovic and his colleagues analyzed publicly-available whole exome, transcriptome, and clinical data from 718 multiple myeloma patients (doi: 10.1371/journal.pgen.1007087). They used both genetic analysis and self-reporting to determine ancestry for all patients. Manojlovic excluded three patients for whom their genetic and self-reported racial identities did not align. The population ultimately included 127 patients of African descent and 591 patients of European descent.
It’s the heterogeneity of the study population that makes these findings so important, Manojlovic said. “This CoMMpass study…really pushed the boundaries of population heterogeneity. The fact that we had 127 African Americans in this study, that’s unprecedented.”
And it enabled new findings. TP53, a tumor suppressor gene known to be active in many cancers, has been implicated in multiple myeloma specifically. But when Manojlovic ran MutSig, a mutation significance tool developed by the Broad, on the African American population, TP53 did not come up at all. “P53 didn’t show up; it wasn’t even of any significance. What happened? What’s going on? Where is it?” he recounts. “I looked and there was only one mutation in 130 patients. I was quite shocked. Then I re-ran in the Caucasian population and sure enough it popped up.”
In fact, the researchers found that multiple myeloma patients of European descent were six times more likely than their African-descent counterparts to have mutations in TP53. But that higher mutation rate does not result in worse clinical outcome. The American Cancer Society estimates that 30,000 new cases of multiple myeloma will be diagnosed in the U.S. this year, and that nearly 13,000 patients will die from it. African American patients are three times more likely to be diagnosed with this type of cancer and twice as likely to die from it than Caucasians of the same age and gender.
The researchers did identify new cancer gene mutations that are significantly more prevalent in African Americans, linking these genes to multiple myeloma for the first time. One of them in particular, IRF4, is known to promote oncogenic fusions. “This one may have a target already possibly available. It has implications for immunomodulatory agents to work on it,” he said. These agents haven’t been used for multiple myeloma treatment in the past, Manojlovic said, but the study’s findings suggest that for African American patients, different treatment routes would be necessary.
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” said John D. Carpten, Chair of the Department of Translational Genomics and senior author of the paper. “The new candidate myeloma genes we identified in the African American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”