Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States and one of the most heritable cancers. A family history of the disease is perhaps the best defined risk factor, and approximately 15-20% of CLL patients have a family member with CLL or a related lymphoproliferative disorder. Much effort has been devoted to trying to elucidate the mechanisms underlying this genetic risk. Familial CLL appears to be clinically and biologically similar to sporadic CLL, and most if not all CLL appears to be preceded by monoclonal B-cell lymphocytosis (MBL), which does appear to occur at higher frequency in relatives in families with CLL. Neither linkage studies nor candidate gene association studies have proven particularly informative in CLL, but genomewide association studies have identified multiple low-risk variants that together explain about 16% of the familial risk of CLL. Studies of individual families have identified higher-risk single nucleotide polymorphisms or copy number variants associated with disease risk in those families. Current efforts to identify additional risk loci are focused on applying next-generation sequencing to the germline of informative CLL families as well as individuals with sporadic CLL.