Clonal growth and prediction of monoclonal B-cell lymphocytosis - ABSTRACT Monoclonal B-cell lymphocytosis (MBL) is a precancerous state affecting 8-10 million adults with no existing cancer control strategies. As a precursor to chronic lymphocytic leukemia (CLL), MBL is characterized by the presence of monoclonal B-cell clones in the peripheral blood of otherwise healthy individuals. Early evidence supports that MBL increases risk of adverse clinical outcomes, including progression to CLL requiring therapy, development of other hematological and solid cancers, hospitalizations due to serious infections, and reduced humoral immune response to vaccinations. However, the scale and diversity of MBL studies is currently limited by the need for flow cytometric analysis of peripheral blood mononuclear cells to diagnose MBL. These biospecimens are rarely available in large biobanking or cohort studies that could otherwise allow more comprehensive and well-powered investigation of the causes and consequences of MBL, especially in populations of diverse ancestries. We propose to overcome these limitations by developing and validating a strategy to predict MBL status (Aim 1). In brief, we propose using existing genotyping array data, that is readily available in many biobanks, to identify mosaic chromosomal alterations (mCAs), which affect large segments of DNA and include gains, losses, and copy number-neutral loss of heterozygosity events. Recent work in biobank studies has established mCAs as a potent risk factor for lymphoid malignancies but MBL is also a major risk factor of lymphoid malignancies, and thus the question of how mCAs relate to MBL is unknown. We have collected the largest cohort of individuals with MBL and genetic data, and in our preliminary analyses, we found that autosomal mCAs are associated with risk of MBL with an odds ratio of 50.5 (95% confidence interval 36.5-70.6, P = 1.34x10-152) with high discrimination. Aim 1 will validate these results, develop a predictive model with other known risk factors for MBL, and then examine generalizability of the model to individuals with strong family history of lymphoid malignancy and to individuals of African ancestry. We further hypothesize that mCAs are drivers of B-cell clone growth. In Aim 2 we will be the first to quantify the incidence of mCAs and the change in cell fraction of mCAs over time from serial peripheral blood samples that have also been screened for MBL. We will then evaluate the relationship between mCAs and growth trajectories of B-cell clones in individuals with MBL. Successful completion of these aims will unlock the ability to study MBL in the largest cohorts in the world, enabling future studies of MBL at an unprecedented scale. As we continue to improve understanding of the consequences of MBL, risk stratification of individuals with MBL will be essential. This proposal will also begin to enable such stratification by characterizing MBL clonal trajectories. Together, these aims will catalyze future studies of MBL to improve understanding of to inform etiologic factors and risk stratification of this prevalent precancer for eventual cancer control.
