Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

Shinichi Yachida; Laura D. Wood; Masami Suzuki; Erina Takai; Yasushi Totoki; Mamoru Kato; Claudio Luchini; Yasuhito Arai; Hiromi Nakamura; Natsuko Hama; Asmaa Elzawahry; Fumie Hosoda; Tomoki Shirota; Nobuhiko Morimoto; Kunio Hori; Jun Funazaki; Hikaru Tanaka; Chigusa Morizane; Takuji Okusaka; Satoshi Nara; Kazuaki Shimada; Nobuyoshi Hiraoka; Hirokazu Taniguchi; Ryota Higuchi; Minoru Oshima; Keiichi Okano; Seiko Hirono; Masamichi Mizuma; Koji Arihiro; Masakazu Yamamoto; Michiaki Unno; Hiroki Yamaue; Matthew J. Weiss; Christopher L. Wolfgang; Toru Furukawa; Hitoshi Nakagama; Bert Vogelstein; Tohru Kiyono; Ralph H. Hruban; Tatsuhiro Shibata

doi:10.1016/j.ccell.2015.12.012

Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

Shinichi Yachida, Laura D. Wood, Masami Suzuki, Erina Takai, Yasushi Totoki, Mamoru Kato, Claudio Luchini, Yasuhito Arai, Hiromi Nakamura, Natsuko Hama, Asmaa Elzawahry, Fumie Hosoda, Tomoki Shirota, Nobuhiko Morimoto, Kunio Hori, Jun Funazaki, Hikaru Tanaka, Chigusa Morizane, Takuji Okusaka, Satoshi NaraKazuaki Shimada, Nobuyoshi Hiraoka, Hirokazu Taniguchi, Ryota Higuchi, Minoru Oshima, Keiichi Okano, Seiko Hirono, Masamichi Mizuma, Koji Arihiro, Masakazu Yamamoto, Michiaki Unno, Hiroki Yamaue, Matthew J. Weiss, Christopher L. Wolfgang, Toru Furukawa, Hitoshi Nakagama, Bert Vogelstein, Tohru Kiyono, Ralph H. Hruban, Tatsuhiro Shibata

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion. Yachida et al. conduct an in-depth genomic analysis on ampullary carcinomas from Japanese and American patient cohorts. This leads to the identification of ELF3 as a driver tumor suppressor and other potentially therapeutically targetable mutations.

Original language	English (US)
Pages (from-to)	229-240
Number of pages	12
Journal	Cancer cell
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2015.12.012
State	Published - Feb 8 2016

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Yachida, S., Wood, L. D., Suzuki, M., Takai, E., Totoki, Y., Kato, M., Luchini, C., Arai, Y., Nakamura, H., Hama, N., Elzawahry, A., Hosoda, F., Shirota, T., Morimoto, N., Hori, K., Funazaki, J., Tanaka, H., Morizane, C., Okusaka, T., ... Shibata, T. (2016). Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. Cancer cell, 29(2), 229-240. https://doi.org/10.1016/j.ccell.2015.12.012

Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. / Yachida, Shinichi; Wood, Laura D.; Suzuki, Masami; Takai, Erina; Totoki, Yasushi; Kato, Mamoru; Luchini, Claudio; Arai, Yasuhito; Nakamura, Hiromi; Hama, Natsuko; Elzawahry, Asmaa; Hosoda, Fumie; Shirota, Tomoki; Morimoto, Nobuhiko; Hori, Kunio; Funazaki, Jun; Tanaka, Hikaru; Morizane, Chigusa; Okusaka, Takuji; Nara, Satoshi; Shimada, Kazuaki; Hiraoka, Nobuyoshi; Taniguchi, Hirokazu; Higuchi, Ryota; Oshima, Minoru; Okano, Keiichi; Hirono, Seiko; Mizuma, Masamichi; Arihiro, Koji; Yamamoto, Masakazu; Unno, Michiaki; Yamaue, Hiroki; Weiss, Matthew J.; Wolfgang, Christopher L.; Furukawa, Toru; Nakagama, Hitoshi; Vogelstein, Bert; Kiyono, Tohru; Hruban, Ralph H.; Shibata, Tatsuhiro.

In: Cancer cell, Vol. 29, No. 2, 08.02.2016, p. 229-240.

Research output: Contribution to journal › Article › peer-review

Yachida, S, Wood, LD, Suzuki, M, Takai, E, Totoki, Y, Kato, M, Luchini, C, Arai, Y, Nakamura, H, Hama, N, Elzawahry, A, Hosoda, F, Shirota, T, Morimoto, N, Hori, K, Funazaki, J, Tanaka, H, Morizane, C, Okusaka, T, Nara, S, Shimada, K, Hiraoka, N, Taniguchi, H, Higuchi, R, Oshima, M, Okano, K, Hirono, S, Mizuma, M, Arihiro, K, Yamamoto, M, Unno, M, Yamaue, H, Weiss, MJ, Wolfgang, CL, Furukawa, T, Nakagama, H, Vogelstein, B, Kiyono, T, Hruban, RH & Shibata, T 2016, 'Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma', Cancer cell, vol. 29, no. 2, pp. 229-240. https://doi.org/10.1016/j.ccell.2015.12.012

Yachida, Shinichi ; Wood, Laura D. ; Suzuki, Masami ; Takai, Erina ; Totoki, Yasushi ; Kato, Mamoru ; Luchini, Claudio ; Arai, Yasuhito ; Nakamura, Hiromi ; Hama, Natsuko ; Elzawahry, Asmaa ; Hosoda, Fumie ; Shirota, Tomoki ; Morimoto, Nobuhiko ; Hori, Kunio ; Funazaki, Jun ; Tanaka, Hikaru ; Morizane, Chigusa ; Okusaka, Takuji ; Nara, Satoshi ; Shimada, Kazuaki ; Hiraoka, Nobuyoshi ; Taniguchi, Hirokazu ; Higuchi, Ryota ; Oshima, Minoru ; Okano, Keiichi ; Hirono, Seiko ; Mizuma, Masamichi ; Arihiro, Koji ; Yamamoto, Masakazu ; Unno, Michiaki ; Yamaue, Hiroki ; Weiss, Matthew J. ; Wolfgang, Christopher L. ; Furukawa, Toru ; Nakagama, Hitoshi ; Vogelstein, Bert ; Kiyono, Tohru ; Hruban, Ralph H. ; Shibata, Tatsuhiro. / Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. In: Cancer cell. 2016 ; Vol. 29, No. 2. pp. 229-240.

@article{72608a45c12c4ee985e2a9b3627bbd88,

title = "Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma",

abstract = "Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion. Yachida et al. conduct an in-depth genomic analysis on ampullary carcinomas from Japanese and American patient cohorts. This leads to the identification of ELF3 as a driver tumor suppressor and other potentially therapeutically targetable mutations.",

author = "Shinichi Yachida and Wood, {Laura D.} and Masami Suzuki and Erina Takai and Yasushi Totoki and Mamoru Kato and Claudio Luchini and Yasuhito Arai and Hiromi Nakamura and Natsuko Hama and Asmaa Elzawahry and Fumie Hosoda and Tomoki Shirota and Nobuhiko Morimoto and Kunio Hori and Jun Funazaki and Hikaru Tanaka and Chigusa Morizane and Takuji Okusaka and Satoshi Nara and Kazuaki Shimada and Nobuyoshi Hiraoka and Hirokazu Taniguchi and Ryota Higuchi and Minoru Oshima and Keiichi Okano and Seiko Hirono and Masamichi Mizuma and Koji Arihiro and Masakazu Yamamoto and Michiaki Unno and Hiroki Yamaue and Weiss, {Matthew J.} and Wolfgang, {Christopher L.} and Toru Furukawa and Hitoshi Nakagama and Bert Vogelstein and Tohru Kiyono and Hruban, {Ralph H.} and Tatsuhiro Shibata",

note = "Funding Information: We wish to thank all patients and families who contributed to this study. We are grateful to Ms. Kaho Minoura (Agilent Technologies), Ms. Chika Shima, Ms. Keiko Igarashi, Ms. Risa Usui, Ms. Shoko Ohashi, Ms. Tomoko Urushidate, and Ms. Naoko Okada (National Cancer Center Research Institute) for technical assistance. The authors thank Dr. Hiroyuki Miyoshi (RIKEN, BioResource Center) for lentiviral constructs. This work was supported by the following grants: Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Science and Technology of Japan ( 25134719 to S.Y.; 25134721 to M.K.; 25134720 to T.S.); the Takeda Science Foundation (S.Y.); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (S.Y.); Princess Takamatsu Cancer Research Fund (S.Y.); the National Cancer Center Research and Development Fund (25-A-3 to S.Y.); the Ministry of Health Labor and Welfare (Health and Labor Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer (S.Y., E.T., M.K., C.M., T.O., and T.S.); AIRC grant 12182 (C.L.); Italian Cancer Genome Project ( FIRB RBAP10AHJB ) (C.L.), and the US National Cancer Institutes SPORE grant CA62924 (R.H.H.). The super-computing resource SHIROKANE was provided by the Human Genome Center, The University of Tokyo ( http://sc.hgc.jp/shirokane.html ). Bert Vogelstein is one of the founders of Personal Genome Diagnostics, Inc. and PapGene, Inc., and a member of the Scientific Advisory Board of Sysmex-Inostics. These companies are focused on the identification of genetic alterations in human cancer for diagnostic or therapeutic purposes. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. ",

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day = "8",

doi = "10.1016/j.ccell.2015.12.012",

language = "English (US)",

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pages = "229--240",

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T1 - Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

AU - Yachida, Shinichi

AU - Wood, Laura D.

AU - Suzuki, Masami

AU - Takai, Erina

AU - Totoki, Yasushi

AU - Kato, Mamoru

AU - Luchini, Claudio

AU - Arai, Yasuhito

AU - Nakamura, Hiromi

AU - Hama, Natsuko

AU - Elzawahry, Asmaa

AU - Hosoda, Fumie

AU - Shirota, Tomoki

AU - Morimoto, Nobuhiko

AU - Hori, Kunio

AU - Funazaki, Jun

AU - Tanaka, Hikaru

AU - Morizane, Chigusa

AU - Okusaka, Takuji

AU - Nara, Satoshi

AU - Shimada, Kazuaki

AU - Hiraoka, Nobuyoshi

AU - Taniguchi, Hirokazu

AU - Higuchi, Ryota

AU - Oshima, Minoru

AU - Okano, Keiichi

AU - Hirono, Seiko

AU - Mizuma, Masamichi

AU - Arihiro, Koji

AU - Yamamoto, Masakazu

AU - Unno, Michiaki

AU - Yamaue, Hiroki

AU - Weiss, Matthew J.

AU - Wolfgang, Christopher L.

AU - Furukawa, Toru

AU - Nakagama, Hitoshi

AU - Vogelstein, Bert

AU - Kiyono, Tohru

AU - Hruban, Ralph H.

AU - Shibata, Tatsuhiro

N1 - Funding Information: We wish to thank all patients and families who contributed to this study. We are grateful to Ms. Kaho Minoura (Agilent Technologies), Ms. Chika Shima, Ms. Keiko Igarashi, Ms. Risa Usui, Ms. Shoko Ohashi, Ms. Tomoko Urushidate, and Ms. Naoko Okada (National Cancer Center Research Institute) for technical assistance. The authors thank Dr. Hiroyuki Miyoshi (RIKEN, BioResource Center) for lentiviral constructs. This work was supported by the following grants: Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Science and Technology of Japan ( 25134719 to S.Y.; 25134721 to M.K.; 25134720 to T.S.); the Takeda Science Foundation (S.Y.); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (S.Y.); Princess Takamatsu Cancer Research Fund (S.Y.); the National Cancer Center Research and Development Fund (25-A-3 to S.Y.); the Ministry of Health Labor and Welfare (Health and Labor Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer (S.Y., E.T., M.K., C.M., T.O., and T.S.); AIRC grant 12182 (C.L.); Italian Cancer Genome Project ( FIRB RBAP10AHJB ) (C.L.), and the US National Cancer Institutes SPORE grant CA62924 (R.H.H.). The super-computing resource SHIROKANE was provided by the Human Genome Center, The University of Tokyo ( http://sc.hgc.jp/shirokane.html ). Bert Vogelstein is one of the founders of Personal Genome Diagnostics, Inc. and PapGene, Inc., and a member of the Scientific Advisory Board of Sysmex-Inostics. These companies are focused on the identification of genetic alterations in human cancer for diagnostic or therapeutic purposes. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

PY - 2016/2/8

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N2 - Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion. Yachida et al. conduct an in-depth genomic analysis on ampullary carcinomas from Japanese and American patient cohorts. This leads to the identification of ELF3 as a driver tumor suppressor and other potentially therapeutically targetable mutations.

AB - Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion. Yachida et al. conduct an in-depth genomic analysis on ampullary carcinomas from Japanese and American patient cohorts. This leads to the identification of ELF3 as a driver tumor suppressor and other potentially therapeutically targetable mutations.

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