Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cell lymphocytes. It has a strong genetic component
with 45 inherited single nucleotide polymorphisms (SNPs) identified through genome-wide association studies
(GWAS). Using these SNPs, we computed a polygenic risk score (PRS), which is a weighted average of the
risk alleles across the SNPs with the weights being the log odds ratios from SNP associations, and found that
individuals in the upper quintile had a ~3-fold increased risk of CLL compared to the middle quintile
(P<0.0001), providing evidence that the combination of known and common CLL susceptibility variants is one
of the strongest CLL risk factors. In addition, whole genome and exome sequencing studies have recently
identified over 60 recurrent somatic CLL variants or copy number alterations (CNA) and found that 88-90% of
CLL cases have at least one putative driver mutation and ~44% have at least three driver mutations. However,
little is known about how the inherited genetic variants interact with the tumor (at DNA and RNA level) and their
contribution to tumor evolution. This application proposes to address this knowledge gap. In preliminary data
from our CLL GWAS, we have evidence that a number of the CLL GWAS-discovered SNPs influence the
expression levels of genes in cis (within 1-Mb window around the SNP) using RNA from whole blood or
lymphoblastoid cell lines (LCL). However, because whole blood is a composition of multiple cell types, of
which B-cells make up ~5-10%, B-cell specific signals are most likely missed, and gene expression from cell
lines may be altered by the Epstein Barr Virus transformation used to generate LCL. Aim 1 proposes to
overcome these limitations by using RNA from sorted tumor B-cells, sorted B-cells of healthy controls, and
sorted clonal B-cells from individuals with the precursor condition to CLL, monoclonal B-cell lymphocytosis
(MBL), to perform expression quantitative trait locus (eQTL) analyses. Validation and experimental in vitro
studies will be performed to confirm and evaluate the functional relevance of variants of interest. Next, little is
known about the extent of inherited germline variants in the individuals with somatic driver mutations. Aim 2
will address this gap to assess the relationship between germline and tumor DNA variants and to assess their
effect on CLL outcomes. Finally, CLL is a heterogeneous disease with ~20% of CLL cases having a 5-year
overall survival of 15-19%. There are a number of somatic variants that drive aggressive CLL disease, yet little
is known about the role of inherited variants. Aim 3 will address this gap by identifying novel inherited variants
associated with CLL aggressiveness. Upon completion, we will have identified gene targets of the known CLL
susceptibility SNPs, will have characterized those CLL cases with high or low burden of genomic variants and
assessed the effects on CLL outcomes, and will have gained insight into the genetic contribution to aggressive
CLL. Our results may provide the potential discovery of novel biomarkers for targeted therapies, reveal novel
ways to subclassify CLL, and develop potential genetic counseling strategies for family members.
If you are accessing this page during weekend or evening hours, the database may currently be offline for maintenance and should operational within a few hours. Otherwise, we have been notified of this error and will be addressing it immediately.
Please contact us
if this error persists.
We apologize for the inconvenience.
- The DCCPS Team.