Karen Weintraub Contributor GEN
High Mutation Frequency Does Not Predict Poor Outcome in Certain Patient Cohorts
African-Americans are three times more likely to develop the blood cancer multiple myeloma than people of European descent. They die at twice the rate of Caucasians, too.
But it’s been unclear whether biology was driving those differences or whether socioeconomics or differences in access to care could explain them, John Carpten, Ph.D., director of the Institute of Translational Genomics at the Keck School of Medicine at the University of Southern California, told GEN.
Now, the largest-ever genomic study of African-Americans with multiple myeloma, led by Dr. Carpten, finds that blacks are less likely to carry two dangerous mutations, and more likely to carry three genes that hadn’t been previously recognized as connected to the disease.
The genetic analysis, published Wednesday afternoon in PLoS Genetics, also showed that patients who had the same treatment regimen had the same outcome, regardless of ancestry—suggesting that disparities in care account for the excess number of African-American deaths.
Multiple myeloma has long been a poster child for medical disparities by race, said Daniel Auclair, Ph.D., senior vice president of research at the Multiple Myeloma Research Foundation (MMRF), and an author on the paper. “If you would provide equal access,” he said, African-Americans “should do just as well or maybe even better than non-African-American patients.”
The research relied on publicly available data from the CoMMpass study, sponsored by the MMRF, which aims to follow more than 1,000 newly diagnosed patients during a period of 8 years. The new analysis looked at the genes of both healthy and cancerous cells in 718 of those patients. The study included 127 African-American patients—the largest cohort of its kind ever analyzed—as well as nearly 600 Caucasians.
Among African-Americans, about one-third of their genetic heritage was European, while the vast majority of Caucasians had almost no African ancestry, according to their genetics.
It is well known that race counts, at least in part, for disparities in care and outcomes for other cancers, including prostate, colon, liver, bile duct, and gastric cancers, Carpten said. However, mounting evidence suggests that the biology of genetic ancestry also plays a role. Studies such as CoMMpass will allow researchers to understand the differences in tumor biology from patients of different racial and ancestral backgrounds, he said.
Carpten said CoMMpass is also ideally suited for this kind of analysis, because it will allow researchers to see changes in genetics if cancers progress.
Carpten said he would like to try next to understand why African-Americans appear to be at higher risk for multiple myeloma; and also to look at other minority groups, such as people of Latino descent, who may also be at higher risk. As with African-Americans, there are few datasets large enough to draw conclusions about Latino patients, he said, though he hopes that Keck, in Los Angeles, will eventually draw enough Latinos to allow such an analysis.
Among other steps going forward, Dr. Auclair said the MMRF now plans to analyze the genes newly discovered in African-American patients—BCL7A, BRWD3, and AUTS2—to learn more about their role in multiple myeloma. All three genes have been implicated in other B-cell blood cancers.
“There might be some hidden clues in there,” Dr. Auclair said. “What we learn from African-Americans may become widely applicable even to non-African-American patients who might have the same alterations.”
There are no ongoing drug trials targeted to any of the three genes, the government website clinicaltrials.gov shows. Meanwhile, in the genes that confer added risk to Caucasians with multiple myeloma, there are five trials exploring IRF4—and 144 related to TP53, which, in a recent Nature study, was shown to be the most studied gene of all time. It is often referred to as the “Guardian of the Genome,” as it is the most frequently mutated gene in cancer.
There are so few African-Americans typically included in genetic studies, Carpten said, that it’s unclear—but now worth exploring—whether TP53 is associated with all cancers, or just those in people of European ancestry, he said.
CoMMpass, a $45 million study, has provided the most genomic data now in the public domain for any cancer, Dr. Auclair said. There have been more than 50 talks or posters presented at scientific meetings and 12 papers published out of the data, so far, he said. “This is really a treasure trove of information.”
That’s why the group decided to publish in the open-access PLoS Genetics journal, Auclair said, so no one would have to pay to access the results.