Genomic Abnormalities Among African Individuals with Monoclonal Gammopathies Using Calculated Ancestry
Authors: Baughn Linda B , Larson Dirk , Polley Mei-Yin , Pearce Kathryn E. , Elhaik Eran , Baird Michael L. , Colby Colin , Benson Joanne , Li Zhou , Asmann Yan , Therneau Terry , Cerhan James R. , Vachon Celine M. , Stewart A Keith , Bergsagel P. Leif , Dispenzieri Angela , Kumar Shaji K. , Rajkumar S. Vincent 
Published: October 2019

Abstract
Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-year younger age of onset among African Americans (AA) compared to European Americans (EAs) (Fonseca, Leukemia, 2017). This suggests a possible ancestral-associated genetic predisposition of AAs to the development of monoclonal gammopathies (Landgren, Blood, 2006). When access to care is equal, AAs have a better overall survival compared to EAs suggesting that AAs may have a genetic predisposition that renders them better responders to treatment or have more favorable cytogenetic subtypes of MM (Waxman, Blood, 2010). Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry. We hypothesize that quantifying genetic ancestry is necessary to fully understand the genetic mechanisms of racial disparities of monoclonal gammopathies.
We describe our study of 881 patients with monoclonal gammopathies who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from the bone marrow samples was genotyped on the Precision Medicine Research Array. Biogeographical ancestry was assessed using the Geographic Population Structure Origins tool, which provides the ancestral breakdown of 36 admixture components for each individual representing different geographic regions and outputs admixture proportions corresponding to those ancestries (Elhaik, Nat Commun, 2014). We evaluated whether an increase in the percentage of African Ancestry altered the odds of any primary cytogenetic abnormality. We demonstrated that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting either an t(11;14), t(14;16) or t(14;20) (odds ratio = 1.06, 95% CI: 1.02 - 1.11; p-value = 0.05). Although we observed an increase in the odds of each of the individual translocations with 10% increase in African ancestry, l t(11;14) (OR=1.03) t(14;16) (OR=1.11) and t(14;20) (OR=1.10), these three abnormalities were combined to achieve greater statistical power. The differences in cytogenetic abnormalities were most striking among individuals with ≥80.0% African (n=120) compared to individuals with <0.1% African ancestry (n=235). Using these cutoff values comparing the ≥80.0% and <0.1% African ancestry cohorts, there was a higher prevalence of t(11;14), t(14;16) and t(14;20) (51% vs. 33%, respectively, p-value=0.008) and a lower prevalence of trisomies (with or without IgH translocations) (48.3% vs. 61.3%, respectively, p-value=0.066). In addition, the ≥80% African ancestry cohort also displayed a slightly lower prevalence of monosomy 13/13q deletion compared to the cohort with <0.1% African ancestry (34.2% vs. 38.7%, respectively, p-value=0.021). Further, we observed a significantly higher prevalence in the proportion of females with monoclonal gammopathies among the ≥80% African ancestry cohort compared to the cohort with <0.1% African ancestry (56.7% vs. 42.1%, respectively, p-value=0.028).
We complement our past studies that relied on self-reported race and characterized patients' demographic and uniformly collected cytogenetic data in relation to genetically defined African ancestry. We demonstrate the prevalence of having one of three specific subtypes (i.e., t(11;14), t(14;16), or t(14;20)) was significantly higher in those with highest (≥80%) compared to lowest (<0.1%) African ancestry demonstrating African ancestry is associated with a subtype distribution of MM that differs from non-African individuals. These differences were only revealed after analysis of individuals with the highest and lowest percentage of African ancestry. Since 38.3% of the individuals with ≥80% African ancestry have the favorable t(11;14) translocation (in comparison to 26.8% of <0.1% African individuals), this finding may explain improved survival with equal access to care. Understanding the genetic mechanisms of this disparity is a fundamental step to understanding differences in incidence and outcomes of patients with monoclonal gammopathies.

Disclosures
Elhaik: DNA Diagnostics Center: Consultancy. Baird:DNA Diagnostics Center: Employment. Cerhan:Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kumar:Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.