title: Identification of genomic alterations in oesophageal squamous cell cancer.
abstract: Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.
authors.affiliation: 1] State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China [2].
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Song
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China [2].
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China [2] Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China [3].
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Ou
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China [2].
authors.forename: Zhibo
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authors.lastname: Gao
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China [2].
authors.forename: Enmin
authors.initials: E
authors.lastname: Li
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China [2].
authors.forename: Xiangchun
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authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Weimin
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authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Jiaqian
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authors.lastname: Wang
authors.affiliation: Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Liyan
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authors.lastname: Xu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Yong
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authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Lingyan
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authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Zitong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Xuanlin
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Lijia
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authors.lastname: Dong
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Jie
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authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: He
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Xuehan
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Kunlong
authors.initials: K
authors.lastname: Qiu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Guangliang
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authors.lastname: Yin
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Guangwu
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authors.lastname: Guo
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Qiang
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authors.lastname: Feng
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Peishan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Tumor Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, Guangdong, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Jinyang
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authors.lastname: Zhao
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Longhai
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authors.lastname: Luo
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.affiliation: Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Bainan
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authors.lastname: Xu
authors.affiliation: Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Yingrui
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authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Mingrong
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Zhihua
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authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Dongxin
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authors.lastname: Lin
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
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authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Huanming
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authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, Guangdong 518083, China.
authors.forename: Jun
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authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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authors.lastname: Zhan
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D010641:Phenotype; D051880:Receptors, Notch / Q000235:genetics; D012307:Risk Factors; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; C561887:MIRN548 microRNA, human; D035683:MicroRNAs; D051880:Receptors, Notch