Charles Swanton and colleagues used multiregion exome sequencing to study the evolutionary histories of ten clear cell renal cell carcinomas. They observed marked intratumoral heterogeneity in all cases, with extensive evidence of parallel evolution of tumor subclones and only a small number of truncal driver events. Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development.

Motivation: The study of interactomes, or networks of protein-protein interactions, is increasingly providing valuable information on biological systems. Here we report a study of cancer proteins in an extensive human protein-protein interaction network constructed by computational methods. Results: We show that human proteins translated from known cancer genes exhibit a network topology that is different from that of proteins not documented as being mutated in cancer. In particular, cancer proteins show an increase in the number of proteins they interact with. They also appear to participate in central hubs rather than peripheral ones, mirroring their greater centrality and participation in networks that form the backbone of the proteome. Moreover, we show that cancer proteins contain a high ratio of highly promiscuous structural domains, i.e., domains with a high propensity for mediating protein interactions. These observations indicate an underlying evolutionary distinction between the two groups of proteins, reflecting the central roles of proteins, whose mutations lead to cancer. Contact:paul.bates@cancer.org.uk Supplementary information: The interactome data are available though the PIP (Potential Interactions of Proteins) web server at Author Webpage. Further additional material is available at Author Webpage