Cancer Somatic Driver Mutation Comparative Analyses
Dysregulated cellular growth is a hallmark of cancer, and certain human conditions are associated with both overgrowth and increased cancer risk (see GeneReviews by Eng in Web Resources).45 We therefore next sought to investigate the overlap between the 14 genes and 260 somatically mutated cancer driver genes reported by Lawrence et al.26 There was significant overlap; 8/14 genes involved in OGID were somatically mutated in a diverse range of cancers (NSD1, EZH2, DNMT3A, PTEN, CHD8, HIST1H1E, MTOR, PIK3CA; p = 1.7 × 10−14). For the PI3K/AKT pathway genes, the mutation spectra are similar in OGID and cancer.34 By contrast, for the epigenetic regulation genes, the mutation spectra in OGID and cancer have substantial, distinctive differences.
Somatic mutations in HIST1H1E, EZH2, and DNMT3A occur in hematological malignancies.26, 46, 47, 48, 49, 50 HIST1H1E and EZH2 mutations are each present in ∼20% of B cell lymphomas.48, 49 Somatic HIST1H1E mutations are nonsynonymous mutations throughout the gene and do not include the clustered PTVs that cause OGID (Figure 5). EZH2 mutations in B cell lymphomas are often activating nonsynonymous mutations in the SET domain, the majority of which target a single amino acid, p.Tyr646.48 Nonsynonymous mutations at this residue have not been detected in OGID and are not present in ExAC, perhaps suggesting that germline EZH2 mutations altering p.Tyr646 are not compatible with life (Figure 5). Inactivating EZH2 mutations are present in myeloid malignancies and in T-ALL.46, 47, 48 A proportion of these latter mutations overlap with EZH2 mutations in OGID.
DNMT3A is one of the most frequently mutated genes in AML and mutations also occur less frequently in other hematological malignancies.26, 50 The majority target a single residue, p.Arg882, with the remainder being nonsynonymous variants and PTVs scattered through the gene. Mutations at p.Arg882 have not thus far been reported in OGID (Figure 5). Protein modeling suggests that the somatic mutations primarily impact DNA binding, whereas the mutations in OGID are more likely to impact histone binding.12
Somatic NSD1 mutations are seen in ∼10% of head and neck squamous cell carcinomas26, 51 and somatic CHD8 mutations are present in ∼3% of glioblastoma multiforme (GBM).26 For these cancers the mutation pattern is similar to that observed in OGID, with PTVs being the most frequent mutation type (Figure 5).30 Interestingly, Lawrence et al. found NSD1 and CHD8 to each be significant in their pan-cancer analysis, present in 2% of cancers.26 However, the pan-cancer mutation spectra for each gene was different to that observed in OGID, with most being nonsynonymous mutations scattered throughout the gene (Figure 5).