Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population

Genta Sawada, Atsushi Niida, Ryutaro Uchi, Hidenari Hirata, Teppei Shimamura, Yutaka Suzuki, Yuichi Shiraishi, Kenichi Chiba, Seiya Imoto, Yusuke Takahashi, Takeshi Iwaya, Tomoya Sudo, Tomoatsu Hayashi, Hiroki Takai, Yoshihiro Kawasaki, Takashi Matsukawa, Hidetoshi Eguchi, Keishi Sugimachi, Fumiaki Tanaka, Hiromichi SuzukiKen Yamamoto, Hideshi Ishii, Makiko Shimizu, Hiroshi Yamazaki, Makoto Yamazaki, Yuji Tachimori, Yoshiaki Kajiyama, Shoji Natsugoe, Hiromasa Fujita, Kenichi Mafune, Yoichi Tanaka, David P. Kelsell, Claire A. Scott, Shoji Tsuji, Shinichi Yachida, Tatsuhiro Shibata, Sumio Sugano, Yuichiro Doki, Tetsu Akiyama, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Masaki Mori, Koshi Mimori

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1171-1182
Number of pages12
JournalGastroenterology
Volume150
Issue number5
DOIs
Publication statusPublished - May 1 2016

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Mutation
Population
Japan
Smoking
Esophageal Neoplasms
Alcohol Drinking
Single Nucleotide Polymorphism
Neoplasms
Genetic Epigenesis
Exome
cdc Genes
Thymine
1-Phosphatidylinositol 4-Kinase
Receptor Protein-Tyrosine Kinases
Genetic Polymorphisms
Esophageal Squamous Cell Carcinoma
Transcriptional Activation
Genes
Drinking
Sequence Analysis

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. / Sawada, Genta; Niida, Atsushi; Uchi, Ryutaro; Hirata, Hidenari; Shimamura, Teppei; Suzuki, Yutaka; Shiraishi, Yuichi; Chiba, Kenichi; Imoto, Seiya; Takahashi, Yusuke; Iwaya, Takeshi; Sudo, Tomoya; Hayashi, Tomoatsu; Takai, Hiroki; Kawasaki, Yoshihiro; Matsukawa, Takashi; Eguchi, Hidetoshi; Sugimachi, Keishi; Tanaka, Fumiaki; Suzuki, Hiromichi; Yamamoto, Ken; Ishii, Hideshi; Shimizu, Makiko; Yamazaki, Hiroshi; Yamazaki, Makoto; Tachimori, Yuji; Kajiyama, Yoshiaki; Natsugoe, Shoji; Fujita, Hiromasa; Mafune, Kenichi; Tanaka, Yoichi; Kelsell, David P.; Scott, Claire A.; Tsuji, Shoji; Yachida, Shinichi; Shibata, Tatsuhiro; Sugano, Sumio; Doki, Yuichiro; Akiyama, Tetsu; Aburatani, Hiroyuki; Ogawa, Seishi; Miyano, Satoru; Mori, Masaki; Mimori, Koshi.

In: Gastroenterology, Vol. 150, No. 5, 01.05.2016, p. 1171-1182.

Research output: Contribution to journalArticle

Sawada, G, Niida, A, Uchi, R, Hirata, H, Shimamura, T, Suzuki, Y, Shiraishi, Y, Chiba, K, Imoto, S, Takahashi, Y, Iwaya, T, Sudo, T, Hayashi, T, Takai, H, Kawasaki, Y, Matsukawa, T, Eguchi, H, Sugimachi, K, Tanaka, F, Suzuki, H, Yamamoto, K, Ishii, H, Shimizu, M, Yamazaki, H, Yamazaki, M, Tachimori, Y, Kajiyama, Y, Natsugoe, S, Fujita, H, Mafune, K, Tanaka, Y, Kelsell, DP, Scott, CA, Tsuji, S, Yachida, S, Shibata, T, Sugano, S, Doki, Y, Akiyama, T, Aburatani, H, Ogawa, S, Miyano, S, Mori, M & Mimori, K 2016, 'Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population', Gastroenterology, vol. 150, no. 5, pp. 1171-1182. https://doi.org/10.1053/j.gastro.2016.01.035
Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y et al. Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. Gastroenterology. 2016 May 1;150(5):1171-1182. https://doi.org/10.1053/j.gastro.2016.01.035
Sawada, Genta ; Niida, Atsushi ; Uchi, Ryutaro ; Hirata, Hidenari ; Shimamura, Teppei ; Suzuki, Yutaka ; Shiraishi, Yuichi ; Chiba, Kenichi ; Imoto, Seiya ; Takahashi, Yusuke ; Iwaya, Takeshi ; Sudo, Tomoya ; Hayashi, Tomoatsu ; Takai, Hiroki ; Kawasaki, Yoshihiro ; Matsukawa, Takashi ; Eguchi, Hidetoshi ; Sugimachi, Keishi ; Tanaka, Fumiaki ; Suzuki, Hiromichi ; Yamamoto, Ken ; Ishii, Hideshi ; Shimizu, Makiko ; Yamazaki, Hiroshi ; Yamazaki, Makoto ; Tachimori, Yuji ; Kajiyama, Yoshiaki ; Natsugoe, Shoji ; Fujita, Hiromasa ; Mafune, Kenichi ; Tanaka, Yoichi ; Kelsell, David P. ; Scott, Claire A. ; Tsuji, Shoji ; Yachida, Shinichi ; Shibata, Tatsuhiro ; Sugano, Sumio ; Doki, Yuichiro ; Akiyama, Tetsu ; Aburatani, Hiroyuki ; Ogawa, Seishi ; Miyano, Satoru ; Mori, Masaki ; Mimori, Koshi. / Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. In: Gastroenterology. 2016 ; Vol. 150, No. 5. pp. 1171-1182.
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author = "Genta Sawada and Atsushi Niida and Ryutaro Uchi and Hidenari Hirata and Teppei Shimamura and Yutaka Suzuki and Yuichi Shiraishi and Kenichi Chiba and Seiya Imoto and Yusuke Takahashi and Takeshi Iwaya and Tomoya Sudo and Tomoatsu Hayashi and Hiroki Takai and Yoshihiro Kawasaki and Takashi Matsukawa and Hidetoshi Eguchi and Keishi Sugimachi and Fumiaki Tanaka and Hiromichi Suzuki and Ken Yamamoto and Hideshi Ishii and Makiko Shimizu and Hiroshi Yamazaki and Makoto Yamazaki and Yuji Tachimori and Yoshiaki Kajiyama and Shoji Natsugoe and Hiromasa Fujita and Kenichi Mafune and Yoichi Tanaka and Kelsell, {David P.} and Scott, {Claire A.} and Shoji Tsuji and Shinichi Yachida and Tatsuhiro Shibata and Sumio Sugano and Yuichiro Doki and Tetsu Akiyama and Hiroyuki Aburatani and Seishi Ogawa and Satoru Miyano and Masaki Mori and Koshi Mimori",
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TY - JOUR

T1 - Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population

AU - Sawada, Genta

AU - Niida, Atsushi

AU - Uchi, Ryutaro

AU - Hirata, Hidenari

AU - Shimamura, Teppei

AU - Suzuki, Yutaka

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

AU - Imoto, Seiya

AU - Takahashi, Yusuke

AU - Iwaya, Takeshi

AU - Sudo, Tomoya

AU - Hayashi, Tomoatsu

AU - Takai, Hiroki

AU - Kawasaki, Yoshihiro

AU - Matsukawa, Takashi

AU - Eguchi, Hidetoshi

AU - Sugimachi, Keishi

AU - Tanaka, Fumiaki

AU - Suzuki, Hiromichi

AU - Yamamoto, Ken

AU - Ishii, Hideshi

AU - Shimizu, Makiko

AU - Yamazaki, Hiroshi

AU - Yamazaki, Makoto

AU - Tachimori, Yuji

AU - Kajiyama, Yoshiaki

AU - Natsugoe, Shoji

AU - Fujita, Hiromasa

AU - Mafune, Kenichi

AU - Tanaka, Yoichi

AU - Kelsell, David P.

AU - Scott, Claire A.

AU - Tsuji, Shoji

AU - Yachida, Shinichi

AU - Shibata, Tatsuhiro

AU - Sugano, Sumio

AU - Doki, Yuichiro

AU - Akiyama, Tetsu

AU - Aburatani, Hiroyuki

AU - Ogawa, Seishi

AU - Miyano, Satoru

AU - Mori, Masaki

AU - Mimori, Koshi

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

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