Understanding the mechanisms that govern the formation of precancerous colon lesions, referred to as aberrant crypt foci, and their conversion to fully malignant tumors is a long-term goal of my laboratory. We use chemical carcinogens (indirect-acting methylating agents) to produce colon tumors in sensitive inbred mouse lines that are similar to those associated with 'sporadic' (non-familial) forms of human colon cancer. Our mouse model thus provides us with an experimental system for studying the earliest molecular events associated with this disease. It is also known that heritable characteristics of inbred mice lead either to susceptibility or resistance to formation of colon tumors following exposure to chemical carcinogens. We have shown that benign hyperplastic foci are produced in the distal colons of resistant mouse lines, but these lesions rarely acquire dysplastic features nor progress to carcinomas. We are combining a molecular pathologic approach, using laser capture microscopy, together with gene expression profiling and comparative genomic hybridization, to study the functional characteristics that distinguish hyperplastic and dysplastic lesions. Together with our ongoing studies of specific signaling pathways that are known to contribute to tumor progression, our genetic approach will enable us to predict the tumorigenic potential of human precancerous lesions and to identify candidate genes that may play a role in the pathogenesis of human cancers.