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Characterizing and comparing missense variants in monogenic disease and in cancer

In both monogenic disease and cancer a large fraction of causative mutations are missense, even though these are very different types of disease. Here we examine and compare a number of properties of these mutations in the two classes of disease to determine the extent to which the properties of the mutations are similar or different. Analysis of cancer mutations is complicated by the problem of distinguishing between drivers and passengers. After controlling for this factor in three different ways, we find the following: (1) A very high and similar fraction (~90%) of causal mutations in both diseases are at positions under strong selection pressure. (2) Mutations in structurally disordered regions play a minor role in monogenic disease (only about 10% of mutations are in those regions), but a larger role (about 25%) in cancer, largely because of the higher fraction of disordered regions in cancer driver proteins. (3) A large (~75%) and similar fraction of causal mutations in protein cores in both diseases act by significantly destabilizing three-dimensional structure, implying a large impact on protein function. (4) Cancer oncogene mutations tend to be on the protein surface whereas tumor suppressor and monogenic disease mutations are more common in the core. (5) A surprisingly high fraction (~50%) of mutations in cancer passenger genes are at positions under strong selection pressure.