Genetic Biomarkers for Risk of CLL Progression among high-count MBLs

Monoclonal B-cell lymphocytosis (MBL) is a precursor state to chronic lymphocytic leukemia (CLL), and one of the most common premalignant conditions. MBL is present in 5-10% of the adult population over age 40-years (6-12 million U.S. adults) and is an asymptomatic condition that is characterized by an absolute B-cell count

<5x109/L and no other features of a lymphoproliferative disorder. This condition is subdivided into low-count MBL and high-count (HC) MBL depending on whether the absolute B-cell count is above or below 0.5x109/L. HC MBL individuals progress to develop CLL requiring therapy at a rate of 1-5%/year. Because of the elevated progression risk, clinical practice guidelines recommend that HC MBLs be followed annually for evidence of disease progression (i.e., watch and wait strategy). Although these individuals technically do not have leukemia, this watch and wait strategy causes anxiety and distress. Thus, there is an important need in identifying factors that drive progression among individuals with HC-MBL. In this application we propose to address this need. There is some evidence that biological markers associated with risk of progressive disease in CLL are also associated with risk of progression in HC MBL, including β2-microglobulin and unmutated immunoglobulin heavy chain (IGHV). Moreover, prior whole genome sequencing and whole exome sequencing studies have identified ~60 genes with recurrent somatic variants in CLL patients. Many of these CLL recurrently mutated genes were also found to be mutated in individuals with HC MBL, and in particular, mutations in TP53, NOTCH1, and SF3B1 were found to be associated with progression from HC MBL to CLL. In preliminary data, we found that the total number of recurrently mutated CLL genes [i.e., tumor mutational load (TML)] was prognostic for CLL progression in newly diagnosed HC MBL individuals. In Aim 1 we propose to extent these provocative findings by evaluating the TML with CLL progression in a larger cohort of HC-MBL individuals. In addition to somatic mutations, we and others have identified 41 inherited single nucleotide polymorphisms (SNPs) from 35 loci to be associated with CLL risk through genome-wide association studies. We computed a polygenic risk score (PRS), which is a weighted average of the risk alleles across these SNPs, and found that the PRS is a strong risk factor for both CLL and MBL. In preliminary data we found evidence that this PRS may be associated with progression in CLL. In Aim 2 we propose to further evaluate the PRS with CLL progression among HC MBL individuals. The knowledge gained from this application will provide novel biomarkers for MBL progression to CLL requiring therapy. These results may change current practice guidelines, and in turn, improve quality of life by reducing anxiety and distress for these individuals. As new effective targeted therapies emerge for CLL, there is renewed interest in consideration of early intervention studies. The TML and PRS may be two potential biomarkers for identifying HC MBL individuals who most likely to benefit from such early intervention.