Functional Genomic Characterization of Cancer Genomes

International efforts to sequence cancer genomes now provide an overview of the major genetic alterations that occur in most human cancers. These studies have identified many highly recurrent alterations in specific cancer subtypes but have also identified mutations that occur at lower frequency and unstudied variants of known cancer-associated genes. To elucidate the function of such cancer alleles, we have developed several approaches to systematically interrogate genomic changes found in human tumors. In general, we have taken two complementary approaches. In the first approach, we focus on perturbing genes identified as mutated, amplified, or deleted by cancer genome annotation efforts, whereas in the second, we have taken an unbiased approach to identify genes that are essential for cancer cell proliferation or survival in cell lines that are extensively annotated to identify context-specific essential genes. These studies begin to allow us to define a cancer dependencies map.