Liu Jingwei, Li Hao, Shen Shixuan, Sun Liping, Yuan Yuan, Xing Chengzhong
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
J Cancer. 2018 Apr 19;9(10):1754-1764. doi: 10.7150/jca.24569. eCollection 2018.
Emerging evidence suggested that aberrant alternative splicing (AS) is pervasive event in development and progression of cancer. However, the information of aberrant splicing events involved in colorectal carcinogenesis and progression is still elusive. In this study, splicing data of 499 colon adenocarcinoma cases (COAD) and 176 rectum adenocarcinoma (READ) with clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) to explore the changes of alternative splicing events in relation to the carcinogenesis and prognosis of colorectal cancer (CRC). Gene interaction network construction, functional and pathway enrichment analysis were performed by multiple bioinformatics tools. Overall, most AS patterns were more active in CRC tissues than adjacent normal ones. We detected altogether 35391 AS events of 9084 genes in COAD and 34900 AS events of 9032 genes in READ, some of which were differentially spliced between cancer tissues and normal tissues including genes of SULT1A2, CALD1, DTNA, COL12A1 and TTLL12. Differentially spliced genes were enriched in biological process including muscle organ development, cytoskeleton organization, actin cytoskeleton organization, biological adhesion, and cell adhesion. The integrated predictor model of COAD showed an AUC of 0.805 (sensitivity: 0.734; specificity: 0.756) while READ predictor had an AUC of 0.738 (sensitivity: 0.614; specificity: 0.900). In addition, a number of prognosis-associated AS events were discovered, including genes of PSMD2, NOL8, ALDH4A1, SLC10A7 and PPAT. We draw comprehensive profiles of alternative splicing events in the carcinogenesis and prognosis of CRC. The interaction network and functional connections were constructed to elucidate the underlying mechanisms of alternative splicing in CRC.
新出现的证据表明，异常可变剪接（AS）是癌症发生和发展过程中普遍存在的事件。然而，结直肠癌发生和发展过程中涉及的异常剪接事件的信息仍然难以捉摸。在本研究中，从癌症基因组图谱（TCGA）获取了499例结肠腺癌（COAD）和176例直肠腺癌（READ）的剪接数据以及临床病理信息，以探讨可变剪接事件与结直肠癌（CRC）发生及预后的关系。使用多种生物信息学工具进行基因相互作用网络构建、功能和通路富集分析。总体而言，大多数AS模式在CRC组织中比相邻正常组织更活跃。我们在COAD中总共检测到9084个基因的35391个AS事件，在READ中检测到9032个基因的34900个AS事件，其中一些在癌组织和正常组织之间存在差异剪接，包括SULT1A2、CALD1、DTNA、COL12A1和TTLL12等基因。差异剪接基因富集于生物学过程，包括肌肉器官发育、细胞骨架组织、肌动蛋白细胞骨架组织、生物黏附以及细胞黏附。COAD的综合预测模型的AUC为0.805（敏感性：0.734；特异性：0.756），而READ预测模型的AUC为0.738（敏感性：0.614；特异性：0.900）。此外，还发现了一些与预后相关的AS事件，包括PSMD2、NOL8、ALDH4A1、SLC10A7和PPAT等基因。我们绘制了CRC发生和预后过程中可变剪接事件的综合图谱。构建了相互作用网络和功能连接，以阐明CRC中可变剪接的潜在机制。
