School of Science and Engineering, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Queensland 4558, Australia.
The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China.
Gene. 2019 May 20;697:57-66. doi: 10.1016/j.gene.2019.02.039. Epub 2019 Feb 20.
Oncogenes can potentially cause uncontrolled cell growth, leading to cancer development, and these genes are normally mutated and over-expressed in tumor cells. Genomic alteration of oncogenes might result in oncogenesis and promotion of cancer progression. To date, researchers have focused mainly on the roles of oncogenes in particular cancers, but investigation of oncogenes with gain-of-function mutations in multiple cancer types are less represented in the literature. Furthermore, the effect of those gain-of-function are not validated in gene expression level. To meet this demand, we performed a systematic analysis of gene expression in oncogenes to identify the occurrence of gain-of-function mutations in pan-cancer. We identified 33,551 oncogenic mutations in 5000 samples. From our analysis, we identified three tissues with the highest frequency of gain-of-functional oncogenic mutations in hundreds of samples: breast (739 samples), central nervous system (646 samples) and large intestine (498 samples). By further counting the number of occurrences of oncogenes across cancer types, we identified a list cross-cancer mutational signatures of 99 oncogenes highly mutated in >400 samples in breast, central nervous system and large intestine samples. By further overlapping with gene expression data in the matched tumor samples, we further identified 1875 gain-of-functional mutations/events with consistent gene up-regulation in 1031 samples from multiple cancers. This result may offer additional insight into the relationship between gene dosage and oncogenesis and maybe useful in targeted cancer therapy. In summary, this study provides the first globally examining on the genetic alteration of oncogenes across cancer types. Clinical association analysis has shown that these 99 genes have a significant effect on survival.
癌基因可能导致不受控制的细胞生长，从而引发癌症的发展，这些基因在肿瘤细胞中通常会发生突变和过度表达。癌基因的基因组改变可能导致癌发生和促进癌症进展。迄今为止，研究人员主要关注特定癌症中癌基因的作用，但在文献中，较少涉及具有功能获得性突变的多种癌症类型的癌基因的研究。此外，这些功能获得性的影响在基因表达水平上尚未得到验证。为了满足这一需求，我们对癌基因的基因表达进行了系统分析，以确定泛癌中是否存在功能获得性突变。我们在 5000 个样本中鉴定了 33551 个致癌突变。通过我们的分析，我们在数百个样本中确定了三个具有最高频率功能获得性致癌突变的组织：乳腺（739 个样本）、中枢神经系统（646 个样本）和大肠（498 个样本）。通过进一步计算跨癌症类型的癌基因数量，我们确定了一个在乳腺、中枢神经系统和大肠样本中高度突变的 99 个癌基因的跨癌症突变特征列表，超过 400 个样本。通过与匹配肿瘤样本中的基因表达数据进一步重叠，我们进一步在来自多种癌症的 1031 个样本中确定了 1875 个具有一致基因上调的功能获得性突变/事件。这一结果可能为基因剂量与癌发生之间的关系提供了更多的见解，并且可能对靶向癌症治疗有用。总之，本研究首次对跨癌症类型的癌基因的遗传改变进行了全面研究。临床关联分析表明，这 99 个基因对生存有显著影响。
