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      Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations

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          Abstract

          Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1–E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer.

          Abstract

          Oesophageal squamous-cell carcinoma (ESCC) is a leading cause of cancer death, and half of ESCC cases occur in China. Here, the authors provide an in depth genomic landscape for this disease and identify specific mutation signatures—one of which is linked to alcohol intake.

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          Most cited references 35

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
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            Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

            Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies. Copyright © 2014 Elsevier Inc. All rights reserved.
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              NRF2 and cancer: the good, the bad and the importance of context.

              Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                26 May 2017
                2017
                : 8
                Affiliations
                [1 ]Key Laboratory for Environment and Health (Ministry of Education), School of Public Health, Huazhong University of Science and Technology , No. 13 Hangkong Road, Wuhan 430030, China
                [2 ]Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , No.17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
                [3 ]Cancer Institute, Zhejiang Cancer Hospital , No. 38 Guangji Road, Hangzhou 310022, China
                [4 ]Department of Probability and Statistics, School of Mathematical Sciences and Center for Statistical Science, Peking University , No. 5 Yiheyuan Road, Haidian District, Beijing 100871, China
                [5 ]Department of Genetics, University of North Carolina , Chapel Hill, North Carolina 27599, USA
                [6 ]Department of Biostatistics, University of North Carolina , Chapel Hill, North Carolina 27599, USA
                [7 ]Department of Pathology, Zhejiang Cancer Hospital , No. 38 Guangji Road, Hangzhou 310022, China
                [8 ]Department of Computer Science, University of North Carolina , Chapel Hill, North Carolina 27599, USA
                [9 ]State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , No.17 Panjiayuan nanli, Chaoyang District, Beijing 100021, China
                [10 ]Lineberger Comprehensive Cancer Center, University of North Carolina , Chapel Hill, North Carolina 27599, USA
                [11 ]Department of Thoracic Surgery, Zhejiang Cancer Hospital , No. 38 Guangji Road, Hangzhou 310022, China
                Author notes
                [*]

                These authors contributed equally to this work

                Article
                ncomms15290
                10.1038/ncomms15290
                5477513
                28548104
                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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