Germline and Somatic Genomic Studies in CLL

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States (US) 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 across human populations. 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 other CLL patients, even after controlling for therapy, suggesting that additional factors may exist that may be driving these observed differences. Despite these differences, little is known about the relationship between genomics and CLL pathogenesis across patients in the US. The goal of this application is to expand our understanding of the genetic basis of CLL with the overall hypothesis that genomic features exist that may be associated with the observed differences of incidence, morbidity, and mortality in CLL patients. To test this hypothesis, we will leverage our extensive experience in CLL and applying it to our unique cohort of CLL patients representative to that seen in the US. In Aim 1 we will perform a multi-omic study in our CLL patients and compare the findings with publicly available sequencing data in CLL. With these data, we will be able to characterize the tumor variability and identify novel somatic findings in our unique cohort. In Aim 2, we will evaluate the known CLL susceptibility loci identified through genome wide association studies (GWAS) in our CLL cases and controls in order to provide insight into the generalizability of the CLL known variants. Finally, in Aim 3, we will evaluate the generalizability of our findings that the genomic summary measure, the tumor mutational load, defined as the number of recurrently mutated CLL driver genes, is prognostic in our unique cohort of CLL patients. The knowledge gained from this application may provide novel insight into the biological variability in leukemogenesis, as well as provide understanding of the generalizability of the genetic findings.