The development of both cancer detection techniques and therapeutic strategies benefits tremendously from the identification of novel cancer genes. Since the discovery of oncogenes and tumor suppressor genes, about 300 human cancer genes have been identified. With two drafts of the human genome sequence in hand, it is now appropriate to aim to identify all cancer genes. Speculations on how many cancer genes remain to be found point to relatively high numbers. For example, epidemiological studies suggest there might be as many as 100 unknown genes involved in familial breast cancer. Once identified, novel cancer genes have to be organized into functional pathways and interaction networks. Hence, it is important to develop comprehensive research tools to identify and functionally annotate all cancer genes. It is well accepted that conventional genetics and biochemistry in model organisms such as yeast, nematodes, flies, amphibians, fish and mice can be highly advantageous in the discovery of orthologs of new cancer genes. One of the best illustrations of this statement is the discovery of cyclins and cyclin-dependent kinases in yeasts and sea urchins. Other examples of the role of C. elegans and Drosophila genetics include the elucidation of the Ras pathway and apoptosis. It has recently become clear that functional genomic and proteomic approaches in model organisms are also essential technological components for comprehensive searches for cancer genes. For example, recent work from a few labs including ours suggests that, in C. elegans, genome-wide expression profiling (transcriptome mapping), high-throughput gene knock-out analyses (phoneme mapping) and large-scale protein-protein interaction mapping (interactome mapping) can be used to identify orthologs of potential cancer genes. It has been suggested that such maps could provide even better functional information if they are integrated with each other and together with maps describing where [in what cell(s)] and when (at what stage(s) of development and in response to which external stimulus(i), worm proteins are expressed. In this context, the goals of this grant proposal are to develop innovative technologies for a C. elegans "Localization of Expression Mapping Project" (LEMP). Specifically, we will develop a novel high-throughput and 1 R21 CA97516-01 Marc Vidal, Ph.D. versatile cloning technology to clone worm promoters (R21) and use this technology to clone all worm promoters (R33). Using a complete set of worm promoters, we then propose to develop high-throughput methods to localize gene expression in vivo and initiate a protein-DNA interaction mapping project (R33).