Figure 4

Mutational patterns of atypical tumor suppressor genes and oncogenes. (A) TP53 mutational landscape in uterine corpus endometrial cancer. DOTS-Finder classifies this gene as a TSG as well as an OG. While this gene retains many truncating mutations, which are diffused all over the gene body, it also encompasses a high number of clusterized missense mutations affecting DNA binding. (B) DNMT3A mutational landscape in acute myeloid leukemia. The pattern of mutations shows diffuse truncating mutations and an evident missense cluster on the cytosine C5 DNA methylation domain. The two types of mutations (truncating and missense) do not share the same domains. This pattern could reflect a double mechanism of action of this gene in different patients. (C) SMARCA4 mutational landscape in diffuse large B-cell lymphoma (DLBCL) compared with lung adenocarcinoma (LUAD). SMARCA4 is reported in the literature as a typical loss-of-function TSG and its mutational pattern in lung is consistent with this classification (diffuse truncating mutations). In lymphoma no truncating mutations are called, and half of the missense mutations affect amino acid 973. DOTS-Finder classifies SMARCA4 as a TSG in lung but as an oncogene in lymphoma, following its clustered missense pattern. We suspect a possible dominant negative effect in this second example (Table 3). (D) NPM1 mutational landscape in acute myeloid leukemia. This gene is reported as a gain-of-function oncogene, although it shows a peculiar mutational landscape: 99% of its mutations are truncating, but they are clustered on the carboxyl terminus of amino acid 288. Mutation p.W288fs truncates the protein without deactivating it; NPM1 is instead delocalized from the nucleus to the cytoplasm. The total numbers of truncating sites and missense mutations are indicated. The mutations are mapped on the corresponding canonical protein ideogram, and thus not all the mutations can be represented (for example, splice site mutations are not included in the figure).