Molecular pathways in tumor progression: from discovery to functional understanding

The advent of large scale sequencing methods has enabled analyses of the protein-coding parts of cancer genomes to and the mutated genes that cause common human cancers. Unbiased mutation analyses of human tumors originating in the breast, colon, brain, and pancreas have revealed genomic landscapes composed of a few frequently mutated genes alongside a multitude of infrequently mutated genes. These analyses have revealed a stark heterogeneity in the compendium of mutated genes even among tumors of the same tissue origin, and provide evidence for a larger number of driver mutations during tumorigenesis than hitherto presumed. From the multitude of mutated genes, a limited number of central molecular pathways are emerging. Systems biology approaches will be increasingly important to identify and better de. ne these core pathways. Downstream of genetic analyses, scalable methods for prediction and experimental determination of the phenotypes of mutant alleles and pathways will be instrumental for improved mechanistic understanding of cancer as well as future drug discovery efforts.