Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.
Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.
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DOI：
10.1002/ijc.30068
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发表时间：
2016-07-15
影响因子：
6.4
通讯作者：
Loffredo C
中科院分区：
文献类型：
--
作者：
Al-Hebshi NN;Li S;Nasher AT;El-Setouhy M;Alsanosi R;Blancato J;Loffredo C
该研究旨在确定导致shammah（一种阿拉伯无烟烟草制品）使用者发生口腔鳞状细胞癌（OSCC）的遗传变异。对20个OSCC档案样本进行全外显子组测序，平均深度为127×。使用一种新的，匹配的控制独立的过滤算法确定体细胞突变。CODEX和Exomedepth与一种新的基于基因组变体的过滤器的数据库相结合，用于调用体细胞基因拷贝数变异。用Oncodrive FM和Youn和Simon方法鉴定显著突变的基因。基于基因集富集分析提名候选驱动基因。观察到的突变谱与TCGA项目报告的相似。除了确认已知的OSCC基因外，通过分析确定了几种候选的新驱动事件（TP 53、CDKNA 2、CASP 8、PIK 3CA、HRAS、FAT 1、TP 63、CCND 1和FADD），包括NOTCH 3、CSMD 3、CRB 1、CLTCL 1、OSMR和TRPM 2的突变，原癌基因FOSL 1、RELA、TRAF 6、MDM 2、FRS 2和BAG 1的扩增，以及最近描述的肿瘤抑制物SMARCC 1的缺失。分析还揭示了以前与OSCC无关的途径显着改变，包括Oncostatin-M信号通路、AP-1和C-MYB转录网络以及内吞作用。在有shammah暴露史的样品中，特别是那些测试EBV阳性的样品中，有更高数量的突变、扩增和驱动事件的趋势，表明烟草暴露和EBV之间的相互作用。这项工作为口腔癌的遗传异质性提供了进一步的证据，并表明shammah相关的OSCC的特征是癌基因的广泛扩增。
The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon’s method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes.
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影响因子：
14.9
作者：
Gonzalez-Perez A;Lopez-Bigas N
通讯作者：
Lopez-Bigas N
影响因子：
3.7
作者：
DelBove, Jessica;Rosson, Gary;Weissman, Bernard E.
通讯作者：
Weissman, Bernard E.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4
作者：
Goecks, Jeremy;El-Rayes, Bassel F.;Maithel, Shishir K.;Khoury, H. Jean;Taylor, James;Rossi, Michael R.
通讯作者：
Rossi, Michael R.
影响因子：
14.9
作者：
Jiang Y;Oldridge DA;Diskin SJ;Zhang NR
通讯作者：
Zhang NR