THE GENETICS OF FAMILIAR LEUKEMIA

Familial leukemia is rate, but, as is the case with other cancer famil y syndromes, its study is likely to lead to the identification of gene s causative of the far more common, sporadic cases. I review the clini cal and, what is known of the molecular genetic features of familial l eukemia. I propose a nosology based on whether the leukemia is a compo nent of a medical syndrome or exists as a solitary disease, the appare nt mode of inheritance, and the distribution of leukemia types and sub types 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 anticipati on in familial cases and incorporate epidemiological observations made in sporadic cases. The first model is analogous to trinucleotide repe at expansion in Huntington disease, myotonic dystrophy, and other inhe rited 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 inherit ance of multiple downstream mutations resulting from a defect in a sin gle DNA repair gene.