Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Nucleic Acids Res. 2012 Aug;40(14):6401-13. doi: 10.1093/nar/gks290. Epub 2012 Apr 9.
Cancer-associated mutations in cancer genes constitute a diverse set of mutations associated with the disease. To gain insight into features of the set, substitution, deletion and insertion mutations were analysed at the nucleotide level, from the COSMIC database. The most frequent substitutions were c → t, g → a, g → t, and the most frequent codon changes were to termination codons. Deletions more than insertions, FS (frameshift) indels more than I-F (in-frame) ones, and single-nucleotide indels, were frequent. FS indels cause loss of significant fractions of proteins. The 5'-cut in FS deletions, and 5'-ligation in FS insertions, often occur between pairs of identical bases. Interestingly, the cut-site and 3'-ligation in insertions, and 3'-cut and join-pair in deletions, were each found to be the same significantly often (p < 0.001). It is suggested that these features aid the incorporation of indel mutations. Tumor suppressors undergo larger numbers of mutations, especially disruptive ones, over the entire protein length, to inactivate two alleles. Proto-oncogenes undergo fewer, less-disruptive mutations, in selected protein regions, to activate a single allele. Finally, catalogues, in ranked order, of genes mutated in each cancer, and cancers in which each gene is mutated, were created. The study highlights the nucleotide level preferences and disruptive nature of cancer mutations.
癌症相关基因中的突变构成了一组与疾病相关的多样化突变。为了深入了解该组突变的特征，从 COSMIC 数据库中分析了核苷酸水平的取代、缺失和插入突变。最常见的取代是 c→t、g→a、g→t，最常见的密码子变化是终止密码子。缺失比插入更常见，FS（移码）插入比 I-F（框架内）插入更常见，单核苷酸插入也很常见。FS 插入会导致蛋白质的重要部分丢失。FS 缺失中的 5'-切割和 FS 插入中的 5'-连接经常发生在一对相同的碱基之间。有趣的是，插入中的切割位点和 3'-连接，以及缺失中的 3'-切割和连接对，都被发现同样频繁（p<0.001）。这表明这些特征有助于插入突变的整合。肿瘤抑制基因在整个蛋白质长度上经历更多数量的突变，尤其是破坏性突变，以失活两个等位基因。原癌基因在选定的蛋白质区域经历较少的、破坏性较小的突变，以激活单个等位基因。最后，按等级顺序创建了每个癌症中突变的基因目录，以及每个基因发生突变的癌症目录。该研究强调了癌症突变在核苷酸水平上的偏好和破坏性。
