title: Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population.
abstract: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer.
  
  
  
  We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2. Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells.
  
  
  
  A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5' thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6) factors. Many tumors contained mutations in genes that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7); epigenetic processes (MLL2, EP300, CREBBP, TET2); and the NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase signaling pathways (PIK3CA, EGFR, ERBB2). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes.
  
  
  
  We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Iwate Medical University, Morioka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sudo
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takai
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Neurology, University of Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Esophageal and Gastroenterological Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kajiyama
authors.affiliation: Department of Surgical Oncology and Digestive Surgery, Kagoshima University School of Medicine, Kagoshima, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Surgery, Mitsui Kinen Hospital, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mafune
authors.affiliation: Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Scott
authors.affiliation: Department of Neurology, University of Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.affiliation: Division of Cancer Genomics, Center for Medical Genomics, National Cancer Center Research Institute, Tokyo, Japan; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Genome Science Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan. Electronic address: mmori@gesurg.med.osaka-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan. Electronic address: kmimori@tsurumi.beppu.kyushu-u.ac.jp.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D059472:Exome; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007564:Japan / Q000453:epidemiology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C096127:ALDH2 protein, human; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Copy Number Profiling; Esophagus; Exome Sequencing; Mutational Signature