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NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein\u2010Barr virus (EBV). We envisioned that in\u2010depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty\u2010three NPC paired tumor\/adjacent normal or peripheral blood mononuclear cell samples were deep\u2010sequenced (&gt;1000\u00d7) with respect to a panel of 409 cancer\u2010related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK\/RAS\/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF\u2010\u03baB, and TGF\u2010\u03b2 pathways. In addition, patients harbored CNV among 409 cancer\u2010related genes and missense mutations in TGF\u2010\u03b2\/SMAD signaling were associated with poor overall survival and poor recurrence\u2010free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD\u2010dependent TGF\u2010\u03b2 signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2\/3 and activation of downstream TGF\u2010\u03b2\u2010mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF\u2010\u03b2 signaling contributes to exacerbating the NPC pathogenesis.<\/jats:p>","DOI":"10.1002\/cam4.2429","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T04:44:27Z","timestamp":1563770667000},"page":"5116-5127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Targeted sequencing of cancer\u2010related genes in nasopharyngeal carcinoma identifies mutations in the TGF\u2010\u03b2 pathway"],"prefix":"10.1002","volume":"8","author":[{"given":"An\u2010Ko","family":"Chung","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Chang Gung University Taoyuan City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Nan","family":"OuYang","sequence":"additional","affiliation":[{"name":"Molecular Medicine Research Center Chang Gung University Taoyuan City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Molecular Medicine Research Center Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Department of Biochemistry Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Division of Colon and Rectal Surgery Chang Gung Memorial Hospital Taoyuan City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Chao","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Department of Microbiology and Immunology Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Liver Research Center, Department of Hepato\u2010Gastroenterology Chang Gung Memorial Hospital Taoyuan City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Dung","family":"Luo","sequence":"additional","affiliation":[{"name":"Molecular Medicine Research Center Chang Gung University Taoyuan City Taiwan, Republic of China"},{"name":"Bioinformatics Center Chang Gung University Taoyuan City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Yang","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Information Session, Office of Information Technology Taipei Medical University Taipei City Taiwan, Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen\u2010Jung","family":"Lu","sequence":"additional","affiliation":[{"name":"ACT Genomics, Co. 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