Classification of gastric cancer by molecular profiling

• Project/Area Number: 16K10523
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Shizuoka Cancer Center Research Institute
• Principal Investigator: Terashima Masanori 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (40197794)
• Co-Investigator(Kenkyū-buntansha): 大島 啓一 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (10399587) ; 楠原 正俊 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (40169991)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 外科 / 癌 / ゲノム / マイクロアレイ / 胃癌 / 遺伝子発現 / 遺伝子変異 / 網羅的遺伝子変異解析 / 網羅的遺伝子発現解析

Outline of Final Research Achievements

Whole-exome sequencing and comprehensive gene expression analysis were performed using bold sample, gastric cancer tissue and non-cancerous mucosa in 599 patients with gastric cancer. In gene mutation analysis, TMB high was observed in 14% of the patients. Most frequent gene mutation was observed in TP53 (48 %). TCGA classification was adopted in 250 patients, resulting in EBV in 10 patients (1 %), MSI in 34 patients (14 %), CIN 10 119 patients (48 %), GS in 87 patients (35 %). There were significant differences of relapse-free survival among the subgroup.
In patients received adjuvant chemotherapy, immune regulatory genes were identified as prognostic factor. In addition, over expression of MAGEA10 was observed in patients with liver metastasis and MAGEA10 was identified as prognostic factor for relapse-free survival.

Academic Significance and Societal Importance of the Research Achievements

本研究により本邦の胃癌遺伝子プロファイリングの同定が可能となった。その結果、わが国ではEBVやMSIの頻度が低く、CINの頻度が高い事が明らかとなった。今後、わが国独自の分類が必要となる事が示唆された。また、本邦では胃癌手術補助化学療法としてS-1が用いられているが、今回の研究により、術後補助化学療法においても免疫関連遺伝子が予後因子となることが明らかとされた。今後の免疫チェックポイント阻害剤の術後補助化学療法への応用に期待がもてる結果であった。更に、術後肝転移再発症例ではMAGEA10の高発現が認められた。これらのアプローチにより進行胃癌の治療成績の向上がもたらされる事が期待される。

Research Products

• [Journal Article] Current status of perioperative chemotherapy for locally advanced gastric cancer and JCOG perspectives (2020)
  • Author(s): Terashima Masanori、Yoshikawa Takaki、Boku Narikazu、Ito Seiji、Tsuburaya Akira、Iwasaki Yoshiaki、Fukagawa Takeo、Tokunaga Masanori、Sano Takeshi、Sasako Mitsuru、the Stomach Cancer Study Group, Japan Clinical Oncology Group
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 50 Issue: 5 Pages: 528-534
  • DOI: 10.1093/jjco/hyaa005
  • Peer Reviewed
• [Journal Article] Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients. (2020)
  • Author(s): Nagashima T, Yamaguchi K, Terashima M, et al.
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 687-699
  • DOI: 10.1111/cas.14290
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomic profiling of gastric cancer tissues identified potential biomarkers for predicting peritoneal recurrence. (2020)
  • Author(s): Kaji S, Irino T, Kusuhara M, Makuuchi R, Yamakawa Y, Tokunaga M, Tanizawa Y, Bando E, Kawamura T, Kami K, Ohashi Y, Zhang S, Orita H, Lee-Okada HC, Fukunaga T, Terashima M.
  • Journal Title: Gastric Cancer Volume: - Issue: 5 Pages: 874-883
  • DOI: 10.1007/s10120-020-01065-5
  • NAID: 40022329548
  • Peer Reviewed
• [Journal Article] Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors. (2020)
  • Author(s): Fujiya K, Ohshima K, Kitagawa Y, Hatakeyama K, Nagashima T, Aizawa D, Sugino T, Urakami K, Yamaguchi K, Terashima M.
  • Journal Title: Eur J Surg Oncol. Volume: - Issue: 6 Pages: 1080-1087
  • DOI: 10.1016/j.ejso.2020.02.036
  • Peer Reviewed
• [Journal Article] Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors. (2019)
  • Author(s): Ohshima K, Fujiya K, Nagashima T, Ohnami S, Hatakeyama K, Urakami K, Naruoka A, Watanabe Y, Moromizato S, Shimoda Y, Ohnami S, Serizawa M, Akiyama Y, Kusuhara M, Mochizuki T, Sugino T, Shiomi A, Tsubosa Y, Uesaka K, Terashima M, Yamaguchi K.
  • Journal Title: Cancer Science Volume: 110 Issue: 12 Pages: 3821-3833
  • DOI: 10.1111/cas.14202
  • Peer Reviewed
• [Journal Article] Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501) (2019)
  • Author(s): Terashima Masanori、Iwasaki Yoshiaki、Mizusawa Junki、Katayama Hiroshi、Nakamura Kenichi、Katai Hitoshi、Yoshikawa Takaki、Ito Yuichi、Kaji Masahide、Kimura Yutaka、Hirao Motohiro、Yamada Makoto、Kurita Akira、Takagi Masakazu、Boku Narikazu、Sano Takeshi、Sasako Mitsuru
  • Journal Title: Gastric Cancer Volume: 印刷中 Issue: 5 Pages: 1044-1052
  • DOI: 10.1007/s10120-019-00941-z
  • Peer Reviewed
• [Journal Article] Impact of Malnutrition After Gastrectomy for Gastric Cancer on Long-Term Survival (2018)
  • Author(s): Fujiya Keiichi、Kawamura Taiichi、Omae Katsuhiro、Makuuchi Rie、Irino Tomoyuki、Tokunaga Masanori、Tanizawa Yutaka、Bando Etsuro、Terashima Masanori
  • Journal Title: Annals of Surgical Oncology Volume: 25 Issue: 4 Pages: 974-983
  • DOI: 10.1245/s10434-018-6342-8
  • Peer Reviewed
• [Journal Article] Long-Term Outcomes of Gastric Cancer Patients with Preoperative Sarcopenia (2018)
  • Author(s): Kawamura Taiichi、Makuuchi Rie、Tokunaga Masanori、Tanizawa Yutaka、Bando Etsuro、Yasui Hiroshi、Aoyama Takashi、Inano Toshimi、Terashima Masanori
  • Journal Title: Annals of Surgical Oncology Volume: 25 Issue: 6 Pages: 1625-1632
  • DOI: 10.1245/s10434-018-6452-3
  • Peer Reviewed
• [Journal Article] Metabolome analysis of esophageal cancer tissues using capillary electrophoresis-time-of-flight mass spectrometry. (2018)
  • Author(s): Tokunaga M, Kusuhara M, Terashima M, et al
  • Journal Title: Int J Oncol. Volume: 52 Pages: 1947-1958
  • DOI: 10.3892/ijo.2018.4340
  • Peer Reviewed
• [Journal Article] Immune response-associated gene profiling in Japanese melanoma patients using multi-omics analysis (2017)
  • Author(s): Akiyama Yasuto、Kiyohara Yoshio、Yoshikawa Shusuke、Otsuka Masaki、Kondou Ryota、Nonomura Chizu、Miyata Haruo、Iizuka Akira、Ashizawa Tadashi、Ohshima Keiichi、Urakami Kenichi、Nagashima Takeshi、Kusuhara Masatoshi、Sugino Takashi、Yamaguchi Ken
  • Journal Title: Oncology Reports Volume: 39 Pages: 1125-1131
  • DOI: 10.3892/or.2017.6173
  • Peer Reviewed / Open Access
• [Journal Article] <b>CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected </b><b>tissues </b> (2017)
  • Author(s): Yamakawa Y, Kusuhara M, Terashima M, Kinugasa Y, Sugino T, Abe M, Mochizuki T, Hatakeyama K, Kami K, Yamaguchi K.
  • Journal Title: Biomedical Research Volume: 38 Issue: 1 Pages: 41-52
  • DOI: 10.2220/biomedres.38.41
  • NAID: 130005242922
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <b>Comprehensive analysis of gene mutation and expression profiles in neuroendocrine carcinomas of the </b><b>stomach </b> (2017)
  • Author(s): Makuuchi R, Terashima M, Kusuhara M, Nakajima T, Serizawa M, Hatakeyama K, Ohshima K, Urakami K, Yamaguchi K.
  • Journal Title: Biomedical Research Volume: 38 Issue: 1 Pages: 19-27
  • DOI: 10.2220/biomedres.38.19
  • NAID: 130005242938
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] <b>Prevalence of low-penetrant germline </b><i><b>TP53</b></i><b> D49H mutation in Japanese cancer </b><b>patients </b> (2016)
  • Author(s): Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, Ichiyama T, Oka A, Kishi T, Kimura S, Kubota M, Takanashi J, Takahashi Y, Tamai H, Natsume J, Hamano S, Hirabayashi S, Maegaki Y, Mizuguchi M, Minagawa K, Yoshikawa H, Kira J, Kusunoki S, Hara T.
  • Journal Title: Biomedical Research Volume: 37 Issue: 4 Pages: 259-264
  • DOI: 10.2220/biomedres.37.259
  • NAID: 130005405218
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 胃癌におけるT cell inflamed gene expression signatureを用いた phenotypeの解析 (2019)
  • Author(s): 中村健一, 畠山慶一, 古川健一朗, 藤谷啓一, 神谷諭, 日景允, 谷澤豊, 坂東悦郎, 山口建, 寺島雅典
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] 胃腺がん高頻度変異症例の分子プロファイリング (2019)
  • Author(s): 古川健一朗, 畠山慶一, 神谷愉, 日景允, 谷澤豊, 坂東悦郎, 杉浦禎一, 塩見明生, 寺島雅典, 山口建
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] 日本人における胃癌の分子生物学的特徴 (2019)
  • Author(s): 藤谷啓一, 芹澤昌邦, 大島啓一, 長嶋剛史, 浦上研一, 秋山靖人, 山口建, 寺島雅典
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] 胃癌におけるImmune signatureとPD-L1発現とtumor mutation burdenの関係について (2019)
  • Author(s): 中村健一, 畠山慶一, 永田雅人, 小関佑介, 脇悠平, 古川健一朗, 藤谷啓一, 神谷諭, 日景允, 谷澤豊, 坂東悦郎, 塩見明生, 杉浦禎一, 山口建, 寺島雅典
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] Immune profiles in relation to PD-L1 expression and tumor mutation burden in gastric cancer (2019)
  • Author(s): K. Nakamura, K. Hatakeyama, T. Toriumi, M. Nagata, Y. Koseki, Y. Waki, K. Furukawa, H. Omori, K. Fujiya, S. Kamiya, R. Makuuchi, Y. Tanizawa, E. Bando, M. Terashima
  • Organizer: 13thInternational Gastric Cancer Congress13th INTERNATIONAL GASTRIC CANCER CONGRESS
  • Int'l Joint Research
• [Presentation] Expression patterns of PD-L1 and other immune checkpoint molecules in gastric cancer. (2019)
  • Author(s): Kenichi Nakamura, Keiichi Hatakeyama, Tetsuro Toriumi, Yusuke Koseki, Yuhei Waki, Keiichi Fujiya, Satoshi Kamiya, Rie Makuuchi, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Ken Yamaguchi, Masanori Terashima
  • Organizer: Gastrointestinal cancer Symposium 2019
• [Presentation] 網羅的遺伝子発現解析による胃癌S-1術後補助療法の効果予測に関する検討 (2018)
  • Author(s): 中村健一, 幕内梨恵, 畠山慶一, 杉浦禎一, 山口智弘, 塩見明生, 坂東悦郎, 山口建, 寺島雅典
  • Organizer: 第73回 日本消化器外科学会
• [Presentation] 胃GISTの遺伝情報に基づいた新規バイオマーカーの探索 (2018)
  • Author(s): 藤谷啓一, 楠原正俊, 大島啓一, 幕内梨恵, 入野誠之, 谷澤豊, 坂東悦郎, 川村泰一, 寺島雅典, 山口建
  • Organizer: 第73回 日本消化器外科学会
• [Presentation] 全エキソン解析および全遺伝子発現解析の統合による胃腺癌の分子生物学的分類の検討 (2018)
  • Author(s): 藤谷啓一, 芹澤昌邦, 楠原正俊, 浦研一, 大島啓一, 長嶋剛史, 幕内梨恵, 谷澤豊, 坂東悦郎, 川村泰一, 山口建, 寺島雅典
  • Organizer: 第29回日本消化器癌発生学会
• [Presentation] 胃腺がんhypermutator群の分子プロファイリング (2018)
  • Author(s): 古川健一朗, 畠山慶, 幕内梨恵, 谷澤豊, 坂東悦郎, 川村泰一, 杉浦禎一, 塩見明生, 寺島雅典, 山口建
  • Organizer: 第29回日本消化器癌発生学会
• [Presentation] Perioperative treatment strategies and current studies to improve gastric cancer outcomes in Japan (2018)
  • Author(s): M. Terashima
  • Organizer: 4th International Gastrointestinal Cancer Conference
  • Int'l Joint Research / Invited
• [Presentation] The Cancer Genome Atlas （TCGA）の胃癌分子サブタイプ分類に基づいた日本人胃癌の特徴 (2017)
  • Author(s): 中村健一、幕内梨恵、畠山慶一、浅岡礼人、小関佑介、脇悠平、大森隼人、加治早苗、入野誠之、谷澤豊、坂東悦郎、川村泰一、楠原正敏、杉浦禎一、塩見明生、山口智弘、山口建、寺島雅典
  • Organizer: 第28回日本消化器癌発生学会総会
• [Presentation] 胃癌に対する外科治療の現状と展望 (2017)
  • Author(s): 寺島雅典
  • Organizer: 第55回日本癌治療学会学術集会
  • Invited
• [Presentation] Metabolomic profling in human gastric cancer tissue using capillary electrophoresis time-of-flight mass spectrometry (2017)
  • Author(s): S. Kaji, M. Kusuhara, T. Irino, R. Makuuchi, Y. Yamakawa,Y. Tanizawa, E. Bando, T. Kawamura, K. Kami, Y. Ohashi, M. Terashima
  • Organizer: International Gastric Cancer Congress12th International Gastric Cancer Congress
  • Int'l Joint Research
• [Presentation] 家族歴を有する胃癌の遺伝子解析 (2016)
  • Author(s): 寺島雅典、幕内梨恵、畠山慶一、楠原正俊、堀江泰江、徳永正則、谷澤豊、坂東悦郎、 川村泰一、日景允、加治早苗、絹笠祐介、杉浦禎一、上坂克彦、山口建
  • Organizer: 第54回日本癌治療学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-10-20
• [Presentation] TP53遺伝子変異を加味した新しい胃癌分類の試み (2016)
  • Author(s): 幕内梨恵、畠山慶一、徳永正則、谷澤豊、坂東悦郎、川村泰一、絹笠祐介、杉浦禎一、上坂克彦、大島啓一、浦上研一、楠原正俊、山口建、寺島正典
  • Organizer: 第54回日本癌治療学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-10-20
• [Presentation] Genetic analysis of gastric cancer with distinctive family history (2016)
  • Author(s): M. Terashima, K. Hatakeyama, M. Kusuhara, R. Makuuchi, M. Tokunaga, Y. Tanizawa, E. Bando, T. Kawamura, M. Hikage, S. Kaji, K. Ohshima, S. Ohnami, K. Urakami, K. Yamaguchi
  • Organizer: European Society for Medical Oncology 2016
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-10-07
  • Int'l Joint Research
• [Presentation] New approach to gastric cancer classification based on TP53 mutation (2016)
  • Author(s): R. Makuuchi, K. Hatakeyama, M. Terashima, M. Kusuhara, M. Tokunaga, Y. Tanizawa, E. Bando, T. Kawamura, M. Hikage, S. Kaji, K. Ohshima, S. Ohnami, K. Urakami, K. Yamaguchi
  • Organizer: European Society for Medical Oncology 2016
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-10-07
  • Int'l Joint Research