Grant Number:	5R01CA254951-03 Interpret this number
Primary Investigator:	Slager, Susan
Organization:	Mayo Clinic Rochester
Project Title:	Germline and Somatic Genomic Studies in Cll Minorities
Fiscal Year:	2023

African Americans are significantly underrepresented in cancer research. Although there have been recent efforts toward more inclusion of African Americans in cancer research, substantial work is still needed. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the U.S. with ~21,000 new cases diagnosed each year. CLL is still incurable despite the fact that there have been significant developments in therapeutic interventions with subsequent improvements in outcome. There are initial findings demonstrating differences in molecular and clinical characteristics of CLL patients between African Americans and Caucasians. In particular, African American CLL patients have a younger age of onset, a more aggressive disease at diagnosis, shorter median time to therapy initiation, and reduced overall survival compared to Caucasians, even after controlling for therapy, suggesting that other factors may exist that may be driving this disparity. Despite these differences across these two populations, little is known about the relationship between genomics, race, and CLL pathogenesis. To date, the genetic landscape of CLL has been considerably scrutinized but only among individuals of European descendent. The goal of this application is to directly evaluate the genetic basis of CLL among African Americans with the overall hypothesis that genomic heterogeneity exists between African American and Caucasian populations that may drive, in part, the disparity in risk, morbidity, and mortality in CLL. To test this hypothesis, we will leverage our extensive experience in CLL and applying it to our collection of African American individuals with CLL. In Aim 1 we will perform a multi-omic (genomic, transcriptomic, and epigenomic) study in African American CLL individuals and compare the findings with publicly available sequencing data from Caucasian CLL individuals. With these data, we will be able to characterize the tumor heterogeneity across these two populations and identify novel somatic findings. In Aim 2, we will evaluate the known CLL susceptibility loci identified through genome wide association studies (GWAS) of Caucasians in African American CLL cases and controls in order to provide insight into the differential risk of the index variants and any other variants in the loci across African American and Caucasian populations. Finally, in Aim 3, we will evaluate the generalizability of our recent findings that the genomic summary measure, the tumor mutational load, defined as the number of recurrently mutated CLL driver genes, is prognostic in African American CLLs. The knowledge gained from this application may provide novel insight into the biological differences in leukemogenesis across these two racial group as well as provide understanding of the generalizability of the inherited and somatic genetic findings found in Caucasian CLL to African American CLL. Together these results may improve risk stratification and prognostication among African American CLL cases, and ultimately, they may provide new insights into possible avenues to reduce health disparity in CLL.





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