Understanding the origins of mutations in tumor suppressor genes and oncogenes associated with cancers in different tissues is critical to the development of potential prevention strategies. Analysis of >10,000 nonsense mutations in 63 tumor suppressor genes based on the ratio of the number of nonsense mutations per codon type is reported for each gene. The ratio for C•G→T•A nonsense mutations at Arg CGA codons to the number of CGA codons in all cancers is 23 (3088 total nonsense mutations for 134 CGA codons in the 63 suppressor genes). The ratio for this codon, which is attributed to hydrolytic deamination of 5-methylcytosine at CpG sites based on the sequence context, is 6-fold higher than the next highest ratio that involves a C•G→T•A transition at Trp TGG codons. C•G→A•T transversions at Glu, Ser, Tyr, Gly and Cys codons account for 25 % of the total nonsense mutations but the mutation per codon ratio for these codons is 1.0. Analysis of the bases 5′ of the mutated CGA codons in the 63 tumor suppressor genes in all cancers shows a preference of 5′-G > C ∼ T ∼ A, which is not indicative of a role for enzymatic deamination by deaminases. Overall C•G→T•A mutations account for 61 % of all of the nonsense mutations in the collection of tumor suppressor genes. It is demonstrated that the ratio of C•G→T•A deamination-associated nonsense mutations at CGA codons (hydrolytic deamination) to the number of frame shift insertion/deletion mutations (i.e., replication based) for 5 major tumor suppressors genes are very similar in 3 different tissues that undergo a wide range of stem cell divisions. Therefore, the frequency of deamination mutations parallels the number of stem cell replications. This may reflect the generation of more solvent accessible single-stranded DNA regions during polymerization that are kinetically more prone to deamination.

了解不同组织中与癌症相关的肿瘤抑制基因和癌基因突变的起源对于制定潜在的预防策略至关重要。根据每个基因的每种密码子类型的无义突变数的比率，分析了 63 个肿瘤抑制基因中 >10,000 个无义突变。Arg CGA 密码子的 C•G→T•A 无义突变与所有癌症中的 CGA 密码子数量之比为 23（63 个抑制基因中 134 个 CGA 密码子的总无义突变为 3088 个）。该密码子的比率，归因于基于序列上下文的 CpG 位点处 5-甲基胞嘧啶的水解脱氨基作用，比在 Trp TGG 密码子处涉及 C•G→T•A 转换的下一个最高比率高 6 倍. C•G→A•T 在 Glu、Ser、Tyr、Gly 和 Cys 密码子占总无义突变的 25%，但这些密码子的每个密码子的突变比率为 1.0。对所有癌症中 63 个抑癌基因中突变 CGA 密码子的碱基 5' 的分析表明，5'-G > C ∼ T ∼ A 的偏好，这并不表明脱氨酶的酶促脱氨基作用。总体而言，C•G→T•A 突变占肿瘤抑制基因集合中所有无义突变的 61%。已证明，对于 5 个主要肿瘤抑制基因，CGA 密码子处的 C•G→T•A 脱氨相关无义突变（水解脱氨）与移码插入/缺失突变（即基于复制）的数量之比非常高。在经历广泛的干细胞分裂的 3 种不同组织中相似。所以，脱氨基突变的频率与干细胞复制的数量平行。这可能反映在聚合过程中产生了更多溶剂可及的单链 DNA 区域，这些区域在动力学上更容易脱氨基。