The genetics of familial leukemia

Familial leukemia is rare, but, as is the case with other cancer family syndromes, its study is likely to lead to the identification of genes causative of the far more common, sporadic cases. I review the clinical and, what is known of the molecular genetic features of familial leukemia. I propose a nosology based on whether the leukemia is a component of a medical syndrome or exists as a solitary disease, the apparent mode of inheritance, and the distribution of leukemia types and subtypes in affected family members. I review the recent findings from my group that leukemia is inherited with 'anticipation', in the form of a declining age of onset with each passing generation. I consider two models of leukemia genesis that can potentially account for anticipation in familial cases and incorporate epidemiological observations made in sporadic cases. The first model is analogous to trinucleotide repeat expansion in Huntington disease, myotonic dystrophy, and other inherited neurodegenerative illness demonstrating anticipation. The second model considers evidence that anticipation may be common to multiple types of familial cancer and is based on the intergenerational inheritance of multiple downstream mutations resulting from a defect in a single DNA repair gene.