||5R01CA254951-03 Interpret this number
||Mayo Clinic Rochester
||Germline and Somatic Genomic Studies in Cll Minorities
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.
Differential prognosis of single and multiple TP53 abnormalities in high-count MBL and untreated CLL.
, Wiedmeier-Nutor J.E.
, Parikh S.A.
, McCabe C.E.
, O'Brien D.R.
, Boddicker N.J.
, Kleinstern G.
, Rabe K.G.
, Bruins L.
, Brown S.
, et al.
Blood advances, 2023-07-11; 7(13), p. 3169-3179.
The inherited genetic contribution and polygenic risk score for risk of CLL and MBL: a narrative review.
, Slager S.L.
Leukemia & lymphoma, 2023 Apr; 64(4), p. 788-798.