Genetic Link May Explain Outcomes Differences in Multiple Myeloma in African Americans




We found several very subtle differences in tumors between the two populations [those of European vs African ancestry], but the most striking observation was the higher TP53 mutation occurrence in the patients of European ancestry.
— Zarko Manojlovic, PhD

African Americans are more than twice as likely as their white counterparts to be diagnosed with multiple myeloma, and twice as likely to die from this form of cancer. Research presented at the 9th American Association for Cancer Research (AACR) Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved in Fort Lauderdale looked at a possible genetic link to explain the outcomes differences in myeloma among African Americans.1

“The reason that African Americans have a higher risk for developing multiple myeloma remains unknown,” stated study presenter Zarko Manojlovic, PhD, of the Keck School of Medicine, University of Southern California. “Along with a higher risk of developing multiple myeloma, African Americans also have historically demonstrated a significantly higher mortality rate than white Americans and an earlier age of disease onset.”

In addition, Dr. Manojlovic noted that African Americans have higher levels of phenotypic heterogeneity and monoclonal immunoglobulin levels, which are predisposing risk factors in multiple myeloma. The primary goal of his study was to look at the possible differences in tumors between African Americans and their white counterparts.

“The data I presented at the AACR were on a study that is still ongoing for the next 5 or 6 years. It comprises about 702 individuals with multiple myeloma. Importantly, a relatively large proportion of the cases self-identified as African Americans. We wanted to generate a subpopulation of two cohorts based on genetic ancestry,” explained Dr. Manojlovic.

Study Details

Dr. Manojlovic and his colleagues stratified the patients and used principal component analysis, a technique used to emphasize variation and bring out strong patterns in a dataset, making the data easier to explore and visualize. They also used an analytic tool called ­STRUCTURE. “We drilled down into the data using ancestry-informative markers, which is a set of polymorphisms that exhibit substantially different frequencies between ancestral populations around the world,” said Dr. Manojlovic.

By using these well-established analytic tools, he explained, it helped to avoid multiple confounders associated with using self-reported racial selection. “I stratified the patients strictly along genetic ancestry lines, and for that I used 1,000 Genomes Project data. Through these analyses, we had 142 patients with a high percent of African ancestry and 464 patients with a high percent of European ancestry. We found several very subtle differences in tumors between the two populations, but the most striking observation was the higher TP53 mutation occurrence in the patients of European ancestry. And, to our knowledge, this finding has never been previously reported,” said Dr. Manojlovic.

Different Genetic Findings

He continued: “Our analysis revealed a 7.2% higher occurrence of TP53 mutations in multiple myeloma patients of European ancestry compared with African ancestry, which had a 0% occurrence. This is a significant difference. Additionally, when looking at both TP53 mutation and deletion of the gene locus, only patients of European ancestry had ‘two hits’ in TP53, including mutation of one copy and deletion of the other copy of the gene. The significance of this finding is that TP53 mutations have long been associated with poor overall outcome in patients with multiple myeloma. Thus, the findings would suggest that myeloma patients of European descent have a greater chance of developing high-risk myeloma than their African descent counterparts. Although the largest and most comprehensive of its kind, these results will need to be validated by independent studies.

Mortality Rates

“Historically, it is reported that African Americans with multiple myeloma have a higher mortality rate than white Americans. However, we tested that notion looking at data from a 5-year follow-up. Keep in mind that all of these patients underwent similar therapies, follow-up care, and monitoring,” revealed Dr. Manojlovic.

“Remarkably, when we tested the data, we found no difference in 5-year survival between African American multiple myeloma patients and their white counterparts,” declared Dr. Manojlovic. “In short, when patients were provided with the same quality of care, there were no differences in mortality. This makes our genetic findings even more significant as perhaps with equal treatment in larger, more population-based studies, we might see more equal or perhaps better outcomes in myeloma among African American patients.

Dr. ­Manojlovic noted that the finding about mortality rates may turn the current literature on its head, but he cautioned that it was discovered after a 5-year follow-up and that things may change when the data are examined after 10 years. “These are important findings, which will generate more research into the genetic and disparities-of-care components in multiple myeloma,” concluded Dr. Manojlovic. ■

Disclosure: Dr. Manjlovic reported no potential conflicts of interest.

Reference

1. Manojlovic Z: Comprehensive molecular studies of multiple myeloma in African Americans. 2016 AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved. Presented ­September 26, 2016.



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