Author ORCID Identifier
Date of Graduation
Human and Molecular Genetics
Doctor of Philosophy (PhD)
Michelle A. T. Hildebrandt, Ph.D.
Chad D. Huff, Ph.D.
Ann M. Killary, Ph.D.
Robert Z. Orlowski, M.D., Ph.D.
Susan K. Peterson, Ph.D., M.P.H.
Multiple Myeloma (MM) constitutes 10% of diagnosed hematologic malignancies in the US, with over 12,000 deaths recorded each year. Race/ethnicity is a well-known MM risk factor, where individuals of African descent have over 2- to 3-fold increased risk of incidence compared to those of European descent. Additionally, Hispanics are diagnosed approximately three years younger than white American counterparts, for unknown reasons. Differences in clinical phenotype are also present for MM patients by ancestry, including varying rates of common initiation mutations such as IgH translocations and TP53 mutation between patients of European and African descent. Studies have begun to interrogate the genetic basis for differences in MM susceptibility and other clinical endpoints in populations of European and African lineage. However, there is a gap in our understanding of the genetic etiology of MM susceptibility in Hispanics. Furthermore, MM clinical features have yet to be described in Hispanics, precluding genetic studies of MM clinical outcomes by race/ethnicity.
This study examined the effect of genetic ancestral background on MM susceptibility and clinical endpoints by utilizing the genome-wide genotype dataset and robust medical records of a multi-ethnic patient population seen at MD Anderson Cancer Center. We conducted case-control association analysis in 143 self-identified Hispanic, 211 non-Hispanic black, 262 non-Hispanic white MM cases, and 633 healthy controls. We also described MM clinical characteristics at diagnosis in Hispanic patients and performed a comparative analysis of clinical phenotypes by self-reported ethnicity and genetic ancestry.
We discovered differential risk in MM susceptibility by genetic ancestry. We also identified unique patterns in Hispanics' baseline clinical phenotype compared to self- reported non-Hispanic black and non-Hispanic white patients. Our study also revealed Hispanics with elevated European ancestry to be at an increased risk of genetic abnormalities associated with poor MM prognosis. Moreover, we identified genetic variants within the Wnt/beta-catenin pathway associated with MM risk that vary by race/ethnicity.
Our findings may be clinically applicable to filling the knowledge gap regarding the genetic contributors of MM susceptibility and outcomes in diverse patient populations and towards eliminating self-report bias of race/ethnicity to better define risk associations and better manage patient outcomes.
multiple myeloma, racial/ethnic disparities, genetic ancestry, admixed population structure, Wnt pathway, germline variants, genetic etiology, clinical outcomes, cancer epidemiology