Chronic lymphocytic leukemia (CLL) is a cancer of B-lymphocytes, which expands in the bone marrow, lymph nodes, spleen and blood. While many genes have been implicated in CLL development through sequencing the genome of tumor cells, they do not completely explain the pathogenesis of the disease, nor define the early events that lead the B-cells to proliferate and become cancerous, accumulating the different types of somatic mutations of CLL. Most sequencing studies have focused only on discovery of somatic mutations without investigating germline risk variants. The aim of this project is to identify the landscape of germline risk factors that can predispose an individual to CLL. We will utilize whole-genome and exome-sequencing data on 100 and 500 CLL cases (normal and tumor samples) respectively, from the Spanish CLL consortium (International Cancer Genome Consortium). We will identify recurrent predicted damaging germline mutations. The results from relevant genes will be replicated in a larger cohort of cases and controls. The 20 most important genes accumulating damaging germline mutations in CLL patients (preliminary results involve cell-cycle, DNA damage checkpoint, double-strand break repair genes) will be tested at the functional level to evaluate the nature of the biological processes that are enriched in CLL. We will either use Saccharomyces cerevisiae or cell lines as model systems for functional analyses of the selected genes. We will also then implement other systems, such as Caenorhabditis elegans or Danio rerio models, for which convergent data on mutations in the altered pathways have been obtained. We expect to identify the complete spectrum of susceptibility genes involved in the early stage of development of this type of leukemia and advance the understanding of its pathogenesis.