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      Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

      1 , 2 , 3 , 4 , 2 , 5 , 2 , 6 , 7 , 8 , 5 , 2 , 1 , 1 , 2 , 2 , 2 , 2 , 4 , 2 , 4 , 4 , 8 , 8 , 7 , 2 , 9 , 2 , 6 , 10 , 4 , 4 , 11 , 12 , 11 , 13 , 9 , 6 , 5 , 14 , a , 1 , b , 2

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          Abstract

          Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

          Abstract

          Nasopharyngeal cancer is frequently characterized by Epstein-Barr virus infection. Here, using genomic analyses, the authors find that the tumours harbour mutations in genes involved in the NF-κB signalling pathway or overexpress a viral oncoprotein, latent membrane protein 1.

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          Most cited references 14

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          Focus on nasopharyngeal carcinoma.

           Kwok Lo,  Ka To,  Dolly P Huang (2004)
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            A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.

            The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer. Many studies have reported genomic driver mutations in non-small-cell lung cancers (NSCLCs) over the past decade; however, the molecular pathogenesis of >40% of NSCLCs is still unknown. To identify new molecular targets in NSCLCs, we performed the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue of a 33-yr-old lung adenocarcinoma patient, who is a never-smoker and has no familial cancer history. The cancer showed no known driver mutation in EGFR or KRAS and no EML4-ALK fusion. Here we report a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21. This fusion gene overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation. We identified the KIF5B-RET fusion in two more cases out of 20 primary lung adenocarcinomas in the replication study. Our data demonstrate that a subset of NSCLCs could be caused by a fusion of KIF5B and RET, and suggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer.
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              The genomic landscape of nasopharyngeal carcinoma.

              Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                18 January 2017
                2017
                : 8
                Affiliations
                [1 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, Cancer Program, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, USA
                [2 ]Department of Anatomical & Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong , Hong Kong, China
                [3 ]School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China
                [4 ]Department of Pharmacology and Pharmacy, School of Biomedical Sciences, Li-Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, China
                [5 ]State Key Laboratory of Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong , Hong Kong, China
                [6 ]Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong, China
                [7 ]Department of Computer Science and Engineering, The Chinese University of Hong Kong , Hong Kong, China
                [8 ]Genomic Medicine Institute, Medical Research Center, Seoul National University , Seoul 10-799, Republic of Korea
                [9 ]School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, China
                [10 ]Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong, China
                [11 ]Department of Pathology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania 15261, USA
                [12 ]Institute of Pathology, St. Luke's Medical Center , Quezon City 1112, Philippines
                [13 ]Medical Scientist Training Program, University of Pittsburgh–Carnegie Mellon University , Pittsburgh, Pennsylvania 15261, USA
                [14 ]Department of Otolaryngology, University of California San Francisco , San Francisco, California 94113, USA
                Author notes
                [*]

                These authors contributed equally to this work

                Article
                ncomms14121
                10.1038/ncomms14121
                5253631
                28098136
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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