高精度の分子遺伝学的評価による食道癌治療成績向上のための包括的研究

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21229015
• Research Institution: Osaka University
• Principal Investigator: 森 正樹 大阪大学, 医学系研究科, 教授 (70190999)
• Co-Investigator(Kenkyū-buntansha): 田中 文明 九州大学, 大学病院, 助教 (30332836) ; 夏越 祥次 鹿児島大学, 大学院・医歯学総合研究科, 教授 (70237577) ; 山本 健 九州大学, 生体防御医学研究所, 准教授 (60274528) ; 梶山 美明 順天堂大学, 医学部, 教授 (70241239) ; 藤田 博正 久留米大学, 医学部, 教授 (20129638)
• Keywords: 外科学 / 分子遺伝学 / オミックス医療 / 食道扁平上皮癌

Research Abstract

食道進行癌の治療成績向上のためには癌の発生、進展および治療感受性に関わる因子を総合的かつ俯瞰的に明らかにすることが重要である。食道癌治療成績の向上を具現化するため、平成17年度から基盤研究(S)(以下、前基盤(S)と略称)の助成を頂き、「宿主(遺伝子多型:P)」・「疫学環境(E)」・「腫瘍(T)」を統合した三位一体研究を開始した。本研究ではさらに症例数を増やし、かつ網羅的遺伝子解析を実施することを目的とした。食道癌患者1071人、および健常人2762人から50万SNPs解析を行い、食道癌患者に特異的に変化を有する6SNPsを同定、それらは4q23,12q24.12に集中して存在することがわかった。その連鎖不均衡領域にはアルコール代謝に重要な役割を果たすADH1B,ALDH2遺伝子が存在した。生活習慣とこれらの遺伝子多型との交互作用を検討したところ、飲酒・喫煙が有意に交互作用を持って食道癌罹患と関与することがわかった。これら4つの因子を全く有していない場合と比較して、4つ全ての要素を有する場合、食道癌罹患危険率が357倍高くなること、また喫煙はこれら遺伝子多型の有る無しにかかわらず食道癌罹患に4倍相関するが、飲酒はこれら遺伝子多型を有していなければ食道癌罹患危険度は1.2倍、多型を有していれば12倍、さらに喫煙が加われば62倍となることがわかった。すなわち、この2カ所の遺伝子多型を解析することで、食道癌罹患の予防に有用である可能性が示唆された。切除症例より70例の標本からマイクロダイセクションを行った後に3万遺伝子の網羅的mRNA発現解析、また50万スポットのゲノムCGH解析を行った。現在、臨床病理学的データとの相関を解析中である。

Research Products

• [Journal Article] Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway. (2011)
  • Author(s): Hamano R, Miyata H, Yamasaki M, Kurokawa Y, Hara J, Moon JH, Nakajima K, Takiguchi S, Fujiwara Y, Mori M, Doki Y.
  • Journal Title: Clin Cancer Res Volume: (Epub)
  • Peer Reviewed
• [Journal Article] Prognostic Value of Endoscopic Biopsy Findings After Induction Chemoradiotherapy With and Without Surgery for Esophageal Cancer. (2011)
  • Author(s): Miyata H, Yamasaki M, Takiguchi S, Nakajima K, Fujiwara Y, Konishi K, Morii E, Mori M, Doki Y.
  • Journal Title: Ann Surg Volume: (Epub)
  • Peer Reviewed
• [Journal Article] Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles. (2010)
  • Author(s): Tanaka F, Yamamoto K, Suzuki S, Inoue H, Tsurumaru M, Kajiyama Y, Kato H, Igaki H, Furuta K, Fujita H, Tanaka T, Tanaka Y, Kawashima Y, Natsugoe S, Setoyama T, Tokudome S, Mimori K, Haraguchi N, Ishii H, Mori M.
  • Journal Title: Gut Volume: 59 Pages: 1457-64
  • Peer Reviewed
• [Journal Article] Effects of ghrelin administration after total gastrectomy : a prospective, randomized, placebo-controlled phase II study. (2010)
  • Author(s): Adachi S, Takiguchi S, Okada K, Yamamoto K, Yamasaki M, Miyata H, Nakajima K, Fujiwara Y, Hosoda H, Kangawa K, Mori M, Doki Y.
  • Journal Title: Gastroenterology Volume: 138 Pages: 1312-20
  • Peer Reviewed
• [Journal Article] Defined factors induced reprogramming of gastrointestinal cancer cells. (2010)
  • Author(s): Miyoshi N, Ishii H, Nagai K, Hoshino H, Mimori K, Tanaka F, Nagano H, Sekimoto M, Doki Y, Mori M.
  • Journal Title: Proc Natl Acad Su Volume: 107 Pages: 40-45
  • Peer Reviewed
• [Journal Article] FOXC2 is a Novel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma. (2010)
  • Author(s): Nishida N, Mimori K, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 535-42
  • Peer Reviewed
• [Journal Article] STC2 : a predictive marker for lymph node metastasis in esophageal squamous-cell carcinoma. (2010)
  • Author(s): Kita Y, Mimori K, Iwatsuki M, Yokobori T, Ieta K, Tanaka F, Ishii H, Okumura H, Natsugoe S, Mori M.
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 261-72
  • Peer Reviewed
• [Journal Article] Prediction of the response to chemotherapy in advanced esophageal cancer by gene expression profiling of biopsy samples. (2010)
  • Author(s): Motoori M, Takemasa I, Yamasaki M, Komori T, Takeno A, Miyata H, Takiguchi S, Fujiwara Y, Yasuda T, Yano M, Matsuura N, Matsubara K, Monden M, Mori M, Doki Y.
  • Journal Title: Int J Oncol Volume: 37 Pages: 1113-20
  • Peer Reviewed
• [Journal Article] Utility of response evaluation to neo-adjuvant chemotherapy by (18)F-fluorodeoxyglucose-positron emission tomography in locally advanced esophageal squamous cell carcinoma. (2010)
  • Author(s): Makino T, Miyata H, Yamasaki M, Fujiwara Y, Takiguchi S, Nakajima K, Higuchi I, Hatazawa J, Mori M, Doki Y
  • Journal Title: Surgery Volume: 148(5) Pages: 908-18
  • Peer Reviewed
• [Journal Article] Pre- and post-therapy nodal status equally affects survival of patients with oesophageal squamous cell carcinoma receiving preoperative chemoradiation. (2010)
  • Author(s): Miyata H, Yamasaki M, Takiguchi S, Nakajima K, Fujiwara Y, Mori M, Doki Y.
  • Journal Title: Oncol Rep Volume: 23 Pages: 1331-7
  • Peer Reviewed
• [Journal Article] Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube reconstruction. (2010)
  • Author(s): Yamamoto K, Takiguchi S, Miyata H, Adachi S, Hiura Y, Yamasaki M, Nakajima K, Fujiwara Y, Mori M, Kangawa K, Doki Y.
  • Journal Title: Surgery Volume: 148 Pages: 31-8
  • Peer Reviewed
• [Journal Article] p53 genotype predicts response to chemotherapy in patients with squamous cell carcinoma of the esophagus (2010)
  • Author(s): Yamasaki M, Miyata H, Fujiwara Y, Takiguchi S, Nakajima K, Nishida T, Yasuda T, Matsuyama J, Mori M, Doki Y.
  • Journal Title: Ann Surg Oncol. Volume: 17 Pages: 634-42
  • Peer Reviewed
• [Journal Article] p53 Mutation status predicts pathological response to chemoradiotherapy in locally advanced esophageal cancer. (2010)
  • Author(s): Makino T, Yamasaki M, Miyata H, Yoshioka S, Takiguchi S, Fujiwara Y, Nakajima K, Nishida T, Mori M, Doki Y
  • Journal Title: Ann Surg Oncol. Volume: 17 Pages: 804-11
  • Peer Reviewed
• [Journal Article] High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy. (2010)
  • Author(s): Orita H, Coulter J, Tully E, Abe M, Montgomery E, Alvarez H, Sato K, Hino O, Kaiiyama Y, Tsurumaru M, Gabrielson E.
  • Journal Title: Cancer Biol Ther. Volume: 10 Pages: 549-54
  • Peer Reviewed
• [Journal Article] Study of abnormal chromosome regions in esophageal squamous cell carcinoma by comparative genomic hybridization : relationship of lymph node metastasis and distant metastasis to selected abnormal regions. (2010)
  • Author(s): Sakai N, Kajiyama Y, Iwanuma Y, Tomita N, Amano T, Isayama F, Ouchi K, Tsurumaru M.
  • Journal Title: Dis Esophagus. Volume: 23 Pages: 415-21
  • Peer Reviewed
• [Journal Article] Photodynamic therapy for large superficial squamous cell carcinoma of the esophagus. (2010)
  • Author(s): Tanaka T, Matono S, Nagano T, Murata K, Sueyoshi S, Yamana H, Shirouzu K, Fujita H.
  • Journal Title: Gastrointest Endosc. Volume: 73 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Glucose transporter expression of an esophageal gastrointestinal tumor detected by F-18 FDG PET/CT. (2010)
  • Author(s): Kaida H, Ishibashi M, Yuzuriha M, Kurata S, Arikawa S, Kawahara A, Uozumi J, Uchida M, Kobayashi M, Hirose Y, Fujita H, Kage M, Hayabuchi N.
  • Journal Title: Clin Nucl Med. Volume: 35 Pages: 505-9
  • Peer Reviewed
• [Journal Article] Outcomes of multimodality therapy for stage IVB esophageal cancer with distant organ metastasis (M1-Org) (2010)
  • Author(s): Tanaka T, Fujita H, Matono S, Nagano T, Nishimura K, Murata K, Shirouzu K, Suzuki G, Hayabuchi N, Yamana H.
  • Journal Title: Dis Esophagus Volume: 23 Pages: 646-51
  • Peer Reviewed
• [Journal Article] Pharyngolaryngeal reflux in patients who underwent cervical esophago-gastrostomy following esophagectomy. (2010)
  • Author(s): Nishimura K, Fujita H, Tanaka T, Matono S, Nagano T, Murata K, Umeno H, Yanagawa T, Shirouzu K.
  • Journal Title: Dis Esophagus Volume: 23 Pages: 353-60
  • Peer Reviewed
• [Journal Article] Surgical management for small cell carcinoma of the esophagus. (2010)
  • Author(s): Tanaka T, Matono S, Nagano T, Nishimura K, Murata K, Yamana H, Shirouzu K, Fujita H.
  • Journal Title: Dis Esophagus Volume: 23 Pages: 502-5
  • Peer Reviewed
• [Journal Article] Nuclear expression of 14-3-3 sigma is related to prognosis in patients with esophageal squamous cell carcinoma. (2010)
  • Author(s): Okumura H, Kita Y, Yokomakura N, Uchikado Y, Setoyama T, Sakurai H, Omoto I, Matsumoto M, Owaki T, Ishigami S, Natsugoe S.
  • Journal Title: Anticancer Res Volume: 30 Pages: 5175-9
  • Peer Reviewed
• [Journal Article] Clinical course and outcome after esophagectomy with three-field lymphadenectomy in esophageal cancer. (2010)
  • Author(s): Natsugoe S, Matsumoto M, Okumura H, Uchikado Y, Setoyama T, Sasaki K, Sakurai T, Omoto I, Owaki T, Shinchi H, Ueno S, Ishigami S.
  • Journal Title: Langenbecks Arch Surg Volume: 395 Pages: 341-6
  • Peer Reviewed
• [Journal Article] From uniformed treatment to individualized treatment for superficial esophageal cancer-what is potentially a new approach? (2010)
  • Author(s): Natsugoe S.
  • Journal Title: Ann Thorac Cardiovasc Surg Volume: 16 Pages: 1-7
  • Peer Reviewed
• [Presentation] Strong interaction between alcohol drinking and smoking habits on esophageal squamouse cell carcinoma was observed among only individuals having ADH1B and/or ALDH2 variants (2010)
  • Author(s): Taanka F, Suzuki S, Inoue H, Mimori K, Hideshi I, Mori M
  • Organizer: 第64回日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24
• [Presentation] Strong interaction between alcohol drinking and smoking habits on ESCC was observed among only individuals having ADH1B and/or ALDH2 variants (2010)
  • Author(s): Tanaka F, Yamamoto K, Suzuki S, Inoue H, Koshi Mimori, Ishii H, Mori M, Kiban S team
  • Organizer: 12th World Congress of the International Society for Disease of the Esophagus
  • Place of Presentation: 鹿児島
  • Year and Date: 2010-09-03
• [Presentation] ADH1BまたはALDH2遺伝子多型を有すると、飲酒と喫煙が食道扁平上皮癌罹患により強く相関する (2010)
  • Author(s): 田中文明、山本健、鈴木貞夫、井上裕、主藤朝也、三森功士、柴田浩平、石井秀始、森正樹
  • Organizer: 第64回日本食道学会学術総会
  • Place of Presentation: 久留米
  • Year and Date: 2010-09-01