Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.
Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.
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DOI：
10.1038/s41598-017-00219-3
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发表时间：
2017-04-04
影响因子：
4.6
通讯作者：
Yamaguchi K
中科院分区：
文献类型：
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作者：
Ohshima K;Hatakeyama K;Nagashima T;Watanabe Y;Kanto K;Doi Y;Ide T;Shimoda Y;Tanabe T;Ohnami S;Ohnami S;Serizawa M;Maruyama K;Akiyama Y;Urakami K;Kusuhara M;Mochizuki T;Yamaguchi K
识别驱动基因有助于了解癌症的病因学，对于个体化治疗的发展是必不可少的。基因扩增是肿瘤发生过程中的一件大事。肿瘤特异性扩增依赖性过表达的驱动基因可作为治疗靶点。在这项研究中，我们的目标是通过基因表达和拷贝数的综合分析，在1,454个实体肿瘤中识别依赖于扩增的驱动基因，跨越15种癌症类型。已知的癌基因扩增依赖性过表达在587个肿瘤中(40%)，在结直肠癌中常见的基因是MYC(25%)和MET(18%)，在肺鳞状细胞癌中常见的是Skp2(21%)，在肝癌中是HIST1H3B(19%)和MYCN(13%)，KIT(57%)在胃肠道间质瘤中和FOXL2(12%)在鳞状细胞癌中。在1127个肿瘤中发现138个已知致癌基因和491个已建立的融合基因的基因组异常(78%)。对820个癌症相关基因的进一步分析显示，16个基因是潜在的驱动基因，扩增相关的过度表达仅限于剩余22%的样本(327个肿瘤)最初未确定的遗传驱动因素。其中，编码受体酪氨酸激酶的Ax1在肉瘤中反复过表达和扩增。我们对扩增依赖的过度表达的研究确定了个体肿瘤中潜在的药物靶点。
Identification of driver genes contributes to the understanding of cancer etiology and is imperative for the development of individualized therapies. Gene amplification is a major event in oncogenesis. Driver genes with tumor-specific amplification-dependent overexpression can be therapeutic targets. In this study, we aimed to identify amplification-dependent driver genes in 1,454 solid tumors, across more than 15 cancer types, by integrative analysis of gene expression and copy number. Amplification-dependent overexpression of 64 known driver oncogenes were found in 587 tumors (40%); genes frequently observed were MYC (25%) and MET (18%) in colorectal cancer; SKP2 (21%) in lung squamous cell carcinoma; HIST1H3B (19%) and MYCN (13%) in liver cancer; KIT (57%) in gastrointestinal stromal tumors; and FOXL2 (12%) in squamous cell carcinoma across tissues. Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%). Further analyses of 820 cancer-related genes revealed 16 as potential driver genes, with amplification-dependent overexpression restricted to the remaining 22% of samples (327 tumors) initially undetermined genetic drivers. Among them, AXL, which encodes a receptor tyrosine kinase, was recurrently overexpressed and amplified in sarcomas. Our studies of amplification-dependent overexpression identified potential drug targets in individual tumors.