Identification of lung cancer drivers by comparison of the observed and the expected numbers of missense and nonsense mutations in individual human genes.
Identification of lung cancer drivers by comparison of the observed and the expected numbers of missense and nonsense mutations in individual human genes.
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DOI：
10.18632/oncotarget.28231
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Gorlov, Ivan P
中科院分区：
文献类型：
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作者：
Gorlova, Olga Y;Kimmel, Marek;Tsavachidis, Spiridon;Amos, Christopher I;Gorlov, Ivan P
在很大程度上，癌症的发展是由体细胞突变的获得和积极选择驱动的，这些突变会增加肿瘤细胞的增殖和存活。因此，与癌症发展相关的基因往往含有过多的体细胞突变。基因中过多的错义和/或无义突变是其癌症相关性的指标。为了识别具有过量潜在功能性错义或无义突变的基因，需要比较基因中观察到的突变数量和预期的突变数量。我们使用（i）个体转录本中错义和无义突变的潜在位点数量和（ii）组织学特异性核苷酸背景依赖性突变率来估计个体人类基因中错义和无义突变的预期数量。为了估计突变率（定义为每个肿瘤每个位点的突变数量），我们使用了癌症体细胞突变目录（COSMIC）中报告的沉默突变。估计值依赖于核苷酸背景。我们已经鉴定出 26 个具有过量错义和/或无义突变的肺腺癌基因、18 个小细胞肺癌基因和 26 个肺鳞状细胞癌基因。这些基因包括已知基因和新的肺癌候选基因。
Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the number of potential sites for missense and nonsense mutations in individual transcripts and (ii) histology-specific nucleotide context-dependent mutation rates. To estimate mutation rates defined as the number of mutations per site per tumor we used silent mutations reported in the Catalog Of Somatic Mutations In Cancer (COSMIC). The estimates were nucleotide context dependent. We have identified 26 genes with an excess of missense and/or nonsense mutations for lung adenocarcinoma, 18 genes for small cell lung cancer, and 26 genes for squamous cell carcinoma of the lung. These genes include known genes and novel lung cancer gene candidates.