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综合基因表达和拷贝数分析鉴定了 1454 个实体瘤中扩增依赖性过表达的潜在癌症驱动基因。

Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.

机构信息

Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.

Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.

出版信息

Sci Rep. 2017 Apr 4;7(1):641. doi: 10.1038/s41598-017-00219-3.

DOI:10.1038/s41598-017-00219-3
PMID:28377632
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5428069/
Abstract

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.

摘要

鉴定驱动基因有助于了解癌症的病因，并对开发个体化治疗方法至关重要。基因扩增是致癌过程中的一个主要事件。具有肿瘤特异性扩增依赖性过表达的驱动基因可以成为治疗靶点。在这项研究中，我们旨在通过基因表达和拷贝数的综合分析，鉴定 15 种以上癌症类型的 1454 个实体瘤中的扩增依赖性驱动基因。在 587 个肿瘤（40%）中发现了 64 个已知驱动癌基因的扩增依赖性过表达；在结直肠癌中经常观察到的基因是 MYC（25%）和 MET（18%）；在肺鳞状细胞癌中是 SKP2（21%）；在肝癌中是 HIST1H3B（19%）和 MYCN（13%）；在胃肠道间质瘤中是 KIT（57%）；在鳞状细胞癌中是 FOXL2（12%）。在 1127 个肿瘤（78%）中发现了 138 个已知癌症驱动基因和 491 个已建立的融合基因的基因组异常。对 820 个与癌症相关的基因的进一步分析显示，有 16 个基因可能是潜在的驱动基因，其扩增依赖性过表达仅限于最初未确定遗传驱动因素的其余 22%的样本（327 个肿瘤）。其中，编码受体酪氨酸激酶的 AXL 在肉瘤中经常过表达和扩增。我们对扩增依赖性过表达的研究确定了个体肿瘤中的潜在药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/bae836c1562c/41598_2017_219_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/e49c565b1f4c/41598_2017_219_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/19f6a603085f/41598_2017_219_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/8335d3d7deae/41598_2017_219_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/4041d1649053/41598_2017_219_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/23e75cde391e/41598_2017_219_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/bae836c1562c/41598_2017_219_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/e49c565b1f4c/41598_2017_219_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/19f6a603085f/41598_2017_219_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/8335d3d7deae/41598_2017_219_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/4041d1649053/41598_2017_219_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/23e75cde391e/41598_2017_219_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2d11/5428069/bae836c1562c/41598_2017_219_Fig6_HTML.jpg

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