Integrated multi‐omics data analyses for exploring the co‐occurring and mutually exclusive gene alteration events in colorectal cancer

Human MutationVolume 41, Issue 9 p. 1588-1599 RESEARCH ARTICLE Integrated multi-omics data analyses for exploring the co-occurring and mutually exclusive gene alteration events in colorectal cancer Yuan Zhou, Yuan Zhou Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorXiaoqing Cheng, Xiaoqing Cheng Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorFenglan Zhang, Fenglan Zhang Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorQingqing Chen, Qingqing Chen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorXinyu Chen, Xinyu Chen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorYaojia Shen, Yaojia Shen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorChong Lai, Chong Lai Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorVishnu G. Kota, Vishnu G. Kota Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorWenjie Sun, Wenjie Sun Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorQiong Huang, Qiong Huang The Core Facilities, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorYing Yuan, Ying Yuan Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorJin Wang, Corresponding Author Jin Wang wj7547@163.com Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this authorMaode Lai, Corresponding Author Maode Lai lmp@zju.edu.cn Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this authorDandan Zhang, Corresponding Author Dandan Zhang dandanz@zju.edu.cn orcid.org/0000-0001-5305-9856 Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this author Yuan Zhou, Yuan Zhou Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorXiaoqing Cheng, Xiaoqing Cheng Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorFenglan Zhang, Fenglan Zhang Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorQingqing Chen, Qingqing Chen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorXinyu Chen, Xinyu Chen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorYaojia Shen, Yaojia Shen Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorChong Lai, Chong Lai Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorVishnu G. Kota, Vishnu G. Kota Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorWenjie Sun, Wenjie Sun Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorQiong Huang, Qiong Huang The Core Facilities, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorYing Yuan, Ying Yuan Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaSearch for more papers by this authorJin Wang, Corresponding Author Jin Wang wj7547@163.com Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this authorMaode Lai, Corresponding Author Maode Lai lmp@zju.edu.cn Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this authorDandan Zhang, Corresponding Author Dandan Zhang dandanz@zju.edu.cn orcid.org/0000-0001-5305-9856 Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence Jin Wang, Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang, China. Email: wj7547@163.com Maode Lai, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058 Zhejiang, China. Email: lmp@zju.edu.cn Dandan Zhang, Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 Zhejiang, China. Email: dandanz@zju.edu.cnSearch for more papers by this author First published: 02 June 2020 https://doi.org/10.1002/humu.24059Citations: 5 Yuan Zhou and Xiaoqing Cheng contributed equally to this study. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Co-occurring and mutually exclusive gene alteration events are helpful for understanding carcinogenesis but systematic screening for such events is quite limited. We conducted pairwise screening tests to identify “hit pairs” in colorectal cancer (CRC) by utilizing the cross-omics data from The Cancer Genome Atlas (TCGA). Numerous hit pairs involving somatic mutations, copy number variations, and DNA methylation were found to occur nonrandomly in CRC, such as KRAS and HOXB6, SMAD4 and PMEPA1. Based on these hit pairs, we identified 32 synthetic lethal pairs and 7,527 co-occurring pairs relating to drug response. Our further biological experiments showed that the co-occurrence of mutant FCGBP and NUDT12 silencing (or mutant TMC3 and RPS6KA6 silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations of IRF5 and NEFH, SYNE1 and TTN, or MUC16 and NEFH had worse survival outcomes. Particularly, the presence of mutant SYNE1 and TTN pair not only affects prognosis, but also is related to CRC patients' response to drug treatment. Our “hit pair” genes may provide insights into colorectal carcinogenesis and help open new avenues for CRC therapy. CONFLICT OF INTERESTS The authors declare that there are no conflict of interests. Citing Literature Supporting Information Filename Description humu24059-sup-0001-Supp_Mat.docx2.3 MB Supporting information humu24059-sup-0002-Supp_Mat_Tables.xlsx1.5 MB Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume41, Issue9September 2020Pages 1588-1599 RelatedInformation