The goal of this pilot and feasibility study is to understand the genetic susceptibility to Multiple Myeloma (MM) through the independent and joint effects of select candidate genes in a high-risk African American (AA) population. The hypothesis is that common variation in genes that influence immunoglobulin binding as well as B cell activation and homeostasis correlate with presence of MM. To address this hypothesis, we intend to test whether (1) FCGR2A and candidate genes centromeric and telomeric to this putative susceptibly locus (chromosome 1q21-24) are associated with MM in a high-risk AA population using linkage disequilibrium (LD) to define race-specific haplotype blocks and (2) common variation in candidate genes in the TNF and TNFR superfamily, involved in plasma cell resistance to apoptosis, are associated with susceptibility to MM in a high-risk AA population. Using cases and controls pooled from the University of Alabama at Birmingham (UAB), the Morehouse School of Medicine-Grady Hospital, University of Southern California (USC), University of Washington (UW), Wayne State University and the SEER registry, we intend to exploit targeted genomics relationships of MM susceptibility. The pooled study population will represent the largest population to date of MM among AA patients, which will allow for a comprehensive evaluation of MM susceptibility that is dimorphic by race. Together these approaches offer the best opportunity to rapidly exploit targeted relationships of aberrant B cell activation and homeostasis with MM and to generate preliminary data necessary to investigate functional genomics as a tool for targeting high-risk populations who may benefit from individualized clinical management or therapeutic intervention. The candidate is a new independent investigator without current or past extramural NIH research support who will apply their demonstrated expertise in molecular epidemiology and immunogenetics to the understanding of common pathways involved in the activation of genes important for B cell activation and homeostasis in this enigmatic inflammatory-mediated B cell malignancy. Although much of the work associated with this project will be conducted at UAB, it should be noted that Dr. Elizabeth Brown is a new unfunded investigator with a demonstrated interest in cancer health disparities, having served as co-chairperson for the Women and Minorities Task Force of the Oregon Cancer Center. This project clearly meets one of the goals of the U54, to enhance the cancer disparity research at UAB. The development of the career of a young molecular epidemiologist in cancer disparity at UAB research is critically important to our ultimate understanding of any molecular causes for disparity and to the development of a cancer disparity molecular epidemiology program at UAB. Dr. Reddy at MSM who will serve as a Co-Leader for the project will provide his considerable expertise in characterizing genomic translocations as an important component of this project. Brown's wet laboratory experience is limited and having Dr. Reddy's lab available for training in multiple pertinent laboratory bench techniques is critical to Dr. Brown's training.
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