Mutation frequency and mutation hotspots. (A) Percent of mutations targeting a conserved residue on a gene (hotspot) are plotted versus the total number of mutations found across the gene in the same cancer type. Color-coding indicates the total number of mutations at the hotspot. (B) Mapping of mutation hostpots on the domain architecture of selected proteins. (C) Mapping of missense mutations found in colorectal cancer on the domain architecture and 3D structure of MLL3. Three mutations are mapping on an N-terminal cluster of PHD fingers. Two of the mutations that can be mapped on 3D structures are targeting residues that are necessary for histone binding. Hypermutated genomes were excluded from the analysis as detailed in the Methods section.