Genta Sawada1, Atsushi Niida2, Ryutaro Uchi3, Hidenari Hirata3, Teppei Shimamura2, Yutaka Suzuki4, Yuichi Shiraishi2, Kenichi Chiba2, Seiya Imoto2, Yusuke Takahashi1, Takeshi Iwaya5, Tomoya Sudo3, Tomoatsu Hayashi6, Hiroki Takai6, Yoshihiro Kawasaki6, Takashi Matsukawa7, Hidetoshi Eguchi3, Keishi Sugimachi3, Fumiaki Tanaka3, Hiromichi Suzuki8, Ken Yamamoto9, Hideshi Ishii10, Makiko Shimizu11, Hiroshi Yamazaki11, Makoto Yamazaki10, Yuji Tachimori12, Yoshiaki Kajiyama13, Shoji Natsugoe14, Hiromasa Fujita15, Kenichi Mafune16, Yoichi Tanaka17, David P Kelsell18, Claire A Scott18, Shoji Tsuji7, Shinichi Yachida19, Tatsuhiro Shibata20, Sumio Sugano4, Yuichiro Doki10, Tetsu Akiyama6, Hiroyuki Aburatani21, Seishi Ogawa8, Satoru Miyano2, Masaki Mori22, Koshi Mimori23. 1. Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan. 2. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 3. Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan. 4. Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan. 5. Department of Surgery, Iwate Medical University, Morioka, Japan. 6. Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan. 7. Department of Neurology, University of Tokyo, Japan. 8. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. 9. Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan. 10. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan. 11. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan. 12. Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan. 13. Department of Esophageal and Gastroenterological Surgery, Juntendo University School of Medicine, Tokyo, Japan. 14. Department of Surgical Oncology and Digestive Surgery, Kagoshima University School of Medicine, Kagoshima, Japan. 15. Department of Surgery, Kurume University School of Medicine, Kurume, Japan. 16. Department of Surgery, Mitsui Kinen Hospital, Tokyo, Japan. 17. Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan. 18. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 19. Division of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo, Japan. 20. 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. 21. Genome Science Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. 22. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan. Electronic address: mmori@gesurg.med.osaka-u.ac.jp. 23. Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan. Electronic address: kmimori@tsurumi.beppu.kyushu-u.ac.jp.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND & AIMS: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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Yongjing Liu; Zhaohui Xiong; Andrea Beasley; Thomas D'Amico; Xiaoxin Luke Chen Journal: Ann N Y Acad Sci Date: 2016-07-11 Impact factor: 5.691
Authors: Wenjin Liu; Jeff M Snell; William R Jeck; Katherine A Hoadley; Matthew D Wilkerson; Joel S Parker; Nirali Patel; Yohannie B Mlombe; Gift Mulima; N George Liomba; Lindsey L Wolf; Carol G Shores; Satish Gopal; Norman E Sharpless Journal: JCI Insight Date: 2016-10-06
Authors: Shaohua Ma; Chorlada Paiboonrungruan; Tiansheng Yan; Kevin P Williams; M Ben Major; Xiaoxin Luke Chen Journal: Ann N Y Acad Sci Date: 2018-05-11 Impact factor: 5.691