Inherited predisposition to chronic lymphocytic leukemia.

Inherited susceptibility to chronic lymphocytic leukemia (CLL) has been recognized for decades. Approximately 10% of individuals with CLL report a family history of CLL or a related lymphoproliferative disorder, and genetic predisposition is the best understood risk factor for CLL. Studies of familial CLL have suggested that the disease features are largely similar to sporadic CLL, although recent data suggest that familial CLL may more commonly show somatic hypermutation of the immunoglobulin heavy-chain variable region, suggesting a more indolent disease course. Monoclonal B-cell lymphocytosis (MBL) has been identified recently as a likely precursor to CLL; it is found in the general population with increasing age and enriched in unaffected relatives of individuals with familial CLL. Studies of MBL as well as mouse models of CLL may lead to better understanding of early CLL pathogenesis that is relevant to familial predisposition. To date, the identification of genes that predispose to familial CLL has been slow, primarily due to the relatively few families available for study, the small size of those families and disease causation most likely by multiple genes that each confer smaller risks. In the coming years, the application of systematic genomics approaches to familial CLL should, hopefully, lead to the identification of novel loci involved in the disease.