This proposal outlines a four-year plan utilizing a genetic approach to search for second site tumor modifiers of retinoblastoma (Rb) in the mouse. Strategies will search for both dominant and recessive tumor modifiers. A random germline approach using ethylnitrosourea (ENU) mutagenesis will be employed to search for such mutations. Such methods have been used to isolate the Min (multiple intestinal neoplasia) allele of adenomatous polyposis coli, new PKU mutations as well as defining the Clock mutation in the mouse. Genetic crosses will be done in a way to facilitate mapping of newly acquired mutations that result in retinal tumors. The first and part of the second year will be focused on the mapping of a known modifier locus which affects the number of intestinal tumors in the Min mouse. During this time, mouse strains will be bred to enable the generation of Rb mouse models and identification of second-site Rb- modifiers. The third and fourth years will be devoted to exploring screens for Rb dominant and recessive tumor enhancers using ENU germline mutagenesis. This genetic system has profound potential in not only isolating such tumor enhancers, but also in identifying molecules affecting progression of retinoblastoma. The use of the laboratory mouse would allow methods of somatic and germline mutagenesis, targeted mutagenesis, positional cloning and chimerism to explore a wide spectrum of ocular malignancy and disease.