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Multiple Myeloma Patients of African, European Ancestries Harbor Different Gene Mutations

NEW YORK (GenomeWeb) – Different genes tend to be mutated in multiple myeloma patients of African and European ancestry, a new study has found.

Researchers from the University of Southern California and elsewhere examined the genomes and transcriptomes of more than 700 multiple myeloma patients to determine whether there were molecular differences in disease by patient ancestry. Multiple myeloma occurs more frequently and is more likely to be fatal among African Americans than European Americans.

As the researchers reported today in PLOS Genetics, mutations within BCL7A, BRWD3, and AUTS2 were more common among African-American patients, while TP53 and IRF4 mutations were more frequent among Caucasian patients. As TP53 and IRF4 mutations are associated with poorer prognosis, the researchers said this suggests the increased mortality among African-American patients might not be due to biological factors.

"One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were six times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene," USC's Zarko Manojlovic said in a statement. "Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes."

Senior author John Carpten presented preliminary data on this research at the annual meeting of the American Association for Cancer Research in Washington, DC, in April, when he tried to demonstrate that the lack of diversity in genomic studies can sometimes obscure certain causes of health outcome disparities.

As they reported today, the researchers analyzed data collected from 721 patients participating in the Multiple Myeloma Research Foundation's CoMMpass study, a longitudinal study that aims to genomically profile 1,000 multiple myeloma patients during the course of their treatment. The patients included in this study underwent whole-exome and RNA sequencing of bone marrow tumor extracts and matched normal samples. Patients also reported self-identified race, and the dataset included 128 African Americans and 593 Caucasians.

On average, the researchers generated a mean 124X coverage of the tumor samples and 126X coverage of the germline samples. Rather than relying solely on self-reported race, the researchers conducted a principal components analysis using nearly 5,000 markers of genetic ancestry. From this and an analysis using the software tool STRUCTURE, they uncovered three patients whose self-reported race differed from their genetic ancestry and excluded those patients from their analysis.

Using the MutSig CV algorithm, the researchers found that while African-American and Caucasian patients harbored, on average, the same number of nonsynonymous mutations, which genes were mutated differed.

For instance, the researchers reported that genes such as RYR1, ANKRD26, BCL7A, BRWD3, and AUTS2 had higher mutation rates among African-American multiple myeloma patients. By contrast, mutations in IRF4 and TP53 were significantly more common among Caucasian patients. TP53 mutations were six times more frequent among patients of European ancestry, the researchers reported, adding that the likelihood of a patient harboring a TP53 mutation increased with their percentage of European ancestry.

Both groups harbored similar levels of BRAF mutations, but BRAFE V600E mutations were frequent among Caucasian patients. The researchers verified these mutation frequencies in a separate, previously published cohort of 205 multiple myeloma cases.

As mutations in TP53 and in IRF4 are both indicators of poor prognosis, the researchers noted that they'd expect patients of European descent to have poorer prognosis. But they noted that, contrary to that expectation, clinical outcomes are generally worse for African-American patients. Those worse outcomes could instead be due to socioeconomic factors and limited access to quality healthcare, rather than biological features of the disease, the researchers said.

In addition, three of the genes the researchers found to be commonly mutated among African-American patients — BCL7A, BRWD3, and AUTS2 — hadn't before been linked with multiple myeloma, though they have been associated with other B cell malignancies. The authors noted that these new candidate disease genes might have been overlooked as previous studies of multiple myeloma have relied heavily on patients of European ancestry.