State Key Laboratory of Pharmaceutical Biotechnology, Department of Biology, Nanjing University, Nanjing 210093, China.
BMC Med Genet. 2010 Sep 1;11:128. doi: 10.1186/1471-2350-11-128.
Cancer is clonal proliferation that arises owing to mutations in a subset of genes that confer growth advantage. More and more cancer related genes are found to have accumulated somatic mutations. However, little has been reported about mutational patterns of insertions/deletions (indels) in these genes.
We analyzed indels' abundance and distribution, the relative ratio between indels and somatic base substitutions and the association between those two forms of mutations in a large number of somatic mutations in the Catalogue of Somatic Mutations in Cancer database. We found a strong correlation between indels and base substitutions in cancer-related genes and showed that they tend to concentrate at the same locus in the coding sequences within the same samples. More importantly, a much higher proportion of indels were observed in somatic mutations, as compared to meiotic ones. Furthermore, our analysis demonstrated a great diversity of indels at some loci of cancer-related genes. Particularly in the genes with abundant mutations, the proportion of 3n indels in oncogenes is 7.9 times higher than that in tumor suppressor genes.
There are three distinct patterns of indel distribution in somatic mutations: high proportion, great abundance and non-random distribution. Because of the great influence of indels on gene function (e.g., the effect of frameshift mutation), these patterns indicate that indels are frequently under positive selection and can often be the 'driver mutations' in oncogenesis. Such driver forces can better explain why much less frameshift mutations are in oncogenes while much more in tumor suppressor genes, because of their different function in oncogenesis. These findings contribute to our understanding of mutational patterns and the relationship between indels and cancer.
癌症是克隆性增殖，它源于在赋予生长优势的一组基因中的亚群发生突变。越来越多的癌症相关基因被发现积累了体细胞突变。然而，关于这些基因中插入/缺失（indels）的突变模式却鲜有报道。
我们在大量癌症体细胞突变的 Catalogue of Somatic Mutations in Cancer 数据库中分析了 indels 的丰度和分布、indels 与体细胞碱基替换之间的相对比值，以及这两种突变形式之间的关联。我们发现癌症相关基因中的 indels 与碱基替换之间存在很强的相关性，并表明它们倾向于在同一样本的编码序列中同一基因座集中出现。更重要的是，体细胞突变中的 indels 比例比减数分裂中的要高得多。此外，我们的分析还表明，在一些癌症相关基因的某些基因座上存在着高度多样化的 indels。特别是在突变丰富的基因中，致癌基因中 3n indels 的比例比肿瘤抑制基因高 7.9 倍。
体细胞突变中存在三种不同的 indel 分布模式：高比例、大量和非随机分布。由于 indels 对基因功能的巨大影响（例如，移码突变的影响），这些模式表明 indels 经常受到正向选择，并且通常可以作为致癌作用中的“驱动突变”。这些驱动因素可以更好地解释为什么在致癌基因中很少有移码突变，而在肿瘤抑制基因中却有很多，因为它们在致癌作用中的功能不同。这些发现有助于我们理解突变模式以及 indels 与癌症之间的关系。
