Genetic Predisposition to Chronic Lymphocytic Leukemia (CLL)

Project Summary CLL is the most common leukemia of adults in North America, with about 20,000 new cases per year, and remains incurable. Although a small subset of patients has indolent disease, in the majority of cases CLL is characterized by steady progression toward therapy and once treated, patients are likely to die of the disease or its complications. The primary known risk factor is a family history of the disease, and CLL is one of the most heritable of all cancers, yet the genetic basis of this heritability remains largely unknown. Neither family-based linkage studies nor genomewide association studies (GWAS) have identified clinically useful genetic variants. In our prior work, we hypothesized that the high heritability of CLL may lie in rare germline variants associated with intermediate disease risks, and we identified ATM as the first risk gene for CLL. We further demonstrated that rare germline missense variants in ATM are associated with loss or mutation of the other allele in the tumor, as expected for a cancer predisposition gene. We have since identified these germline ATM variants in 25% of our CLL clinic population, suggesting that ATM may be an important germline driver of CLL. In this grant we will prospectively enroll CLL subjects who have been evaluated for germline ATM variants into a registry that will allow us to determine the association of ATM germline variants with CLL clinical features, development of other cancers and family history of cancer. We will also perform functional assessment of the ATM protein, to determine the impact of the most common and highest risk of these alleles on protein function. Additionally, we will expand the prior analysis that identified ATM, to include all publicly available CLL sequencing data, and employ both a novel highly sensitive variant calling method developed by Google and a novel ancestry matching method. Our preliminary data with this larger cohort and improved methodology have so far confirmed our ATM finding and identified FANCE and CHEK2 as additional CLL risk genes, suggesting a role for other DNA repair genes in CLL susceptibility. We will also focus on higher risk familial CLL with additional exome sequencing, with a similar analysis as above, and with epigenomic profiling with ATAC-seq to explore the non-coding genome. Using a unique cohort of highly impacted families, we will combine ATAC-seq with whole genome and RNA sequencing, to both characterize the gene targets of the GWAS alleles previously identified in CLL, and identify novel noncoding risk variants that impact transcription regulation. This project is feasible because of the rich resources of our unique, well-annotated tissue banks of familial CLL developed over the last 15 years. Our goal with this work is not only to enhance our understanding of the genetic basis of CLL, but also to provide the basis for improved screening and counseling of CLL patients in the clinic, through eventual initiation of clinical trials to assess the utility of genetic testing in this patient population.