Chronic Lymphocytic Leukemia in African Ancestry Population is Characterized by Increased Genomic Instability

Despite the considerable effort to characterize the genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients of European Ancestry (EA), with significant underrepresentation of minorities, including patients of African Ancestry (AA). Furthermore, although over a decade has passed since the initial observations of AA CLL patients suggesting an increased frequency of adverse prognostic factors and inferior clinical outcomes when compared to EA CLL, the differences between populations remain poorly understood. To begin to address this gap, we explored whether ancestry differences exist in the genetic and transcriptomic features of 157 AA and 440 EA individuals diagnosed with CLL. In our study focused on 59 putative driver genes, we found an increased frequency of mutations in driver genes in AA CLL, including mutations in genes of the DNA damage repair (DDR) pathway. Telomere erosion was also increased in AA CLL, amplifying the notion of increased genomic instability in AA CLL. Furthermore, we found enrichment of the Tumor Necrosis Factor-alpha (TNFα) Signaling via NF-κB pathway in AA CLL compared to EA CLL, suggesting that tumor promoting inflammation plays an important role in AA CLL. In summary, we found higher frequency of mutations in genes from the DDR pathway along with shorter telomers and higher transcription of NFkB pathway genes. These results suggest that genomic instability is more prevalent in AA CLL than EA CLL. Future studies are needed to show that it may be a driver of poor prognosis among AA CLL patients.