May 12, 2006
David Hogg, (Senior Scientist, Division of Genomic Medicine, Toronto
Genereal Research Institute, Professor of Medicine, UofT
Developmental second hits and the concept of a mutation field

Knudson's two hit paradigm has driven research in the field of cancer genetics for over thirty years. This model explains many of the molecular and clinical observations in sporadic and familial cancers. However, it fails to predict the phenotypic consequences of second hits that occur during the development of an organism. In familial glomuvenous malformations (GVM), loss of the wild type glomulin allele may produce variable numbers of discrete or clustered lesions. Using data from a set of GVM families, we have developed a mathematical model in which stochastic second hits during various stages of development predict differing spatial distributions of vascular malformations. We show that second hits during development yield a field of mutated cells that are interspersed throughout normal tissue.