Towards systematic functional characterization of cancer genomes

Key Points Cancer genome characterization efforts will provide a complete description of genetic and epigenetic alterations in cancer. However, the complexity and heterogeneity of cancer genomes makes it clear that complementary efforts to understand the function of cancer genes are necessary. The tools to manipulate gene function at genome scale are now available in multiple formats. Technical advances will increase the power and throughput of these approaches. Important functional-genomics approaches include systematic mutagenesis, RNAi, expression libraries and small-molecule screens. Integration of functional and structural characterizations of cancer genomes provides a path to identifying driver genes. These same approaches, tools and methods can also be used to study other diseases. Cancer-genome sequencing is producing vast amounts of information on genetic alterations in tumours, but how can researchers uncover those changes that influence tumorigenesis? This Review describes how large-scale functional-genomics approaches using an increasing range of sophisticated tools offer a way forward. Whole-genome approaches to identify genetic and epigenetic alterations in cancer genomes have begun to provide new insights into the range of molecular events that occurs in human tumours. Although in some cases this knowledge immediately illuminates a path towards diagnostic or therapeutic implementation, the bewildering lists of mutations in each tumour make it clear that systematic functional approaches are also necessary to obtain a comprehensive molecular understanding of cancer. Here we review the current range of methods, assays and approaches for genome-scale interrogation of gene function in cancer. We also discuss the integration of functional-genomics approaches with the outputs from cancer genome sequencing efforts.