Spacial and temporal comics analysis dissolve the evolution and heterogeneity in ESCC.

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04921
• Research Institution: Kyushu University
• Principal Investigator: 三森 功士 九州大学, 大学病院, 教授 (50322748)
• Co-Investigator(Kenkyū-buntansha): 土岐 祐一郎 大阪大学, 医学系研究科, 教授 (20291445) ; 鈴木 穣 東京大学, 大学院新領域創成科学研究科, 教授 (40323646) ; 宮野 悟 東京大学, 医科学研究所, 教授 (50128104) ; 山本 健 久留米大学, 医学部, 教授 (60274528) ; 伊藤 隆司 九州大学, 医学研究院, 教授 (90201326)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 食道がん / メチル化 / LRP1B / LDL受容体 / APOBEC / SNP

Outline of Annual Research Achievements

われわれは先行研究にて、食道扁平上皮癌（ESCC）144症例について全エキソン解析を行い、ドライバー変異と重要なpathwayやsignatureを報告した。本研究ではさらにエピゲノムレベルの解析を併施しESCCの発癌および癌進展における意義を明らかにした。外科的切除を行った術前無治療のESCC90例の癌部と非癌部よりDNAを抽出しbisulfite処理の後、メチル化アレイを行い網羅的に解析、既知のSNPアレイ・全エキソン解析と臨床病理学的因子を合わせた統合プロファイルを作成した。メチル化ステータスに基づいた階層的クラスタリングによって、全症例を３群（高メチル化群、中等度メチル化群、低メチル化群）に分類することが可能であった。次に統合プロファイル解析を行ったところ高メチル化サブグループにおいて、LRP1Bのfocal deletionが高頻度に見出されたが（p=0.04）、飲酒のリスク因子、喫煙習慣などについて特に有意差はない。LRP1BはLDL受容体ファミリーのひとつであるが、その点突然変異は非小細胞肺癌に多く認められ腫瘍形成に関与すると報告されている。他方、扁平上皮癌におけるLRP1B高メチル化が浸潤転移に関与するとの報告もある(Cancer Res 2004, Cancer Sci, 2006)。しかし、臨床病理学的因子で比較してもLRP1B(+)症例は特に有意差を認めていないが、LRP1B focal deletion症例は有意に予後不良であった。リンパ節転移の頻度や分化度にも有意差を認めていない。本研究においてLRP1Bの点突然変異のみならず高メチル化の併存するECSCサブグループは臨床的に高い悪性度を示すことから、LRP1Bが食道発癌から進展に到るまで恒常的に重要な役割を担うことを明らかにした。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] GWAS Identifies Two Novel Colorectal Cancer Loci at 16q24.1 and 20q13.12. (2018)
  • Author(s): Tanikawa C, Kamatani Y, Takahashi A, Momozawa Y, Leveque K, Nagayama S,Mimori K, Mori M, Ishii H, Inazawa J, Yasuda J, Tsuboi A, Shimizu A, Sasaki M, Yamaji T, Sawada N, Iwasaki M, Tsugane S, Naito M, Wakai K, Koyama T, Takezaki T, Yuji K, Murakami Y, Nakamura Y, Kubo M, Matsuda K
  • Journal Title: Carcinogenesis. Volume: Epub Pages: Epub
  • DOI: 10.1093/carcin/bgy026.
  • Peer Reviewed / Open Access
• [Journal Article] Identification of ARL4C as a Peritoneal Dissemination-Associated Gene and Its Clinical Significance in Gastric Cancer. (2018)
  • Author(s): Hu Q, Masuda T, Sato K, Tobo T, Nambara S, Kidogami S, Hayashi N, Kuroda Y, Ito S, Eguchi H, Saeki H, Oki E, Maehara YMimori K
  • Journal Title: Ann Surg Oncol Volume: 25(3) Pages: 745-753
  • DOI: 0.1245/s10434-017-6292-6.
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer (2017)
  • Author(s): Nambara S, Masuda T, Nishio M, Kuramitsu S, Tobo T, Ogawa Y, Hu Q, Iguchi T, Kuroda Y, Ito S, Eguchi H, Sugimachi K, Saeki H, Oki E, Maehara Y, Suzuki A,Mimori K
  • Journal Title: Oncotarget. Volume: 8(64) Pages: 107666-107677
  • DOI: 10.18632/oncotarget.22587
  • Peer Reviewed / Open Access
• [Journal Article] Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer. (2017)
  • Author(s): Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI,Mimori K, Suzuki Y, Hong CP, Ock CY, Kim SJ, Oshima M:
  • Journal Title: Cancer Res. Volume: pii: canres.3303. Pages: canres.3303.
  • DOI: 10.1158/0008-5472.CAN-17-3303.
  • Peer Reviewed / Open Access
• [Journal Article] Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer. (2017)
  • Author(s): Takano Y, Masuda T, Iinuma H, Yamaguchi R, Sato K, Tobo T, Hirata H, Kuroda Y, Nambara S, Hayashi N, Iguchi T, Ito S, Eguchi H, Ochiya T, Yanaga K, Miyano S, Mimori K
  • Journal Title: Oncotarget Volume: . 8(45) Pages: 78598-78613
  • DOI: 10.18632/oncotarget.20009.
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNAs as Biomarkers in Colorectal Cancer. (2017)
  • Author(s): Masuda T, Hayashi N, Kuroda Y, Ito S, Eguchi H, Mimori K
  • Journal Title: Cancers (Basel) Volume: 9(9) Pages: pii: E124.
  • DOI: 10.3390/cancers9090124.
  • Peer Reviewed / Open Access
• [Journal Article] Japanese genome-wide association study identifies a significant colorectal cancer susceptibility locus at chromosome 10p14. (2017)
  • Author(s): Takahashi Y, Sugimachi K, Yamamoto K, Niida A, Shimamura T, Sato T, Watanabe M, Tanaka J, Kudo S, Sugihara K, Hase K, Kusunoki M, Yamada K, Shimada Y, Moriya Y, Suzuki Y, Miyano S, Mori M, Mimori K
  • Journal Title: Cancer Sci Volume: 108(11) Pages: 2239-2247
  • DOI: 10.1111/cas.13391.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma (2017)
  • Author(s): Nambara S, Masuda T, Tobo T, Kidogami S, Komatsu H, Sugimachi K, Saeki H, Oki E, Maehara Y, Mimori K
  • Journal Title: Oncol Lett. Volume: 14(2) Pages: 1795-1801
  • DOI: 10.3892/ol.2017.6341.
  • Peer Reviewed / Open Access
• [Journal Article] 14(1): (2017)
  • Author(s): Sudo T, Takahashi Y, Sawada G, Uchi R, Mimori K, Akagi Y
  • Journal Title: Oncol Lett. Volume: 14(1) Pages: 801-809
  • DOI: 10.3892/ol.2017.6257.
• [Journal Article] DDR2 Expression Is Associated with a High Frequency of Peritoneal Dissemination and Poor Prognosis in Colorectal Cancer (2017)
  • Author(s): Sasaki S, Ueda M, Iguchi T, Kaneko M, Nakayama H, Watanabe T, Sakamoto A, Mimori K
  • Journal Title: Anticancer Res Volume: 37(5) Pages: 2587-2591
  • Peer Reviewed
• [Journal Article] Phosphoserine Phosphatase Is a Novel Prognostic Biomarker on Chromosome 7 in Colorectal Cancer (2017)
  • Author(s): Sato K, Masuda T, Hu Q, Tobo T, Kidogami S, Ogawa Y, Saito T, Nambara S, Komatsu H, Hirata H, Sakimura S, Uchi R, Hayashi N, Iguchi T, Eguchi H, Ito S, Nakagawa T, Mimori K:
  • Journal Title: Anticancer Res Volume: 37(5) Pages: 2365-2371
  • Peer Reviewed
• [Journal Article] Up-regulation of SLC9A9 Promotes Cancer Progression and Is Involved in Poor Prognosis in Colorectal Cancer (2017)
  • Author(s): Ueda M, Iguchi T, Masuda T, Komatsu H, Nambara S, Sakimura S, Hirata H, Uchi R, Eguchi H, Ito S, Sugimachi K, Mizushima T, Doki Y, Mori M, Mimori K
  • Journal Title: Anticancer Res Volume: 37(5) Pages: 2255-2263
  • Peer Reviewed
• [Journal Article] phyC: Clustering cancer evolutionary trees (2017)
  • Author(s): Matsui Y, Niida A, Uchi R, Mimori K, Miyano S, Shimamura T:
  • Journal Title: PLoS Comput Biol. Volume: 13(5) Pages: e1005509
  • DOI: 10.1371/journal.pcbi.1005509.
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of heat-shock factor 1 is associated with a poor prognosis in esophageal squamous cell carcinoma (2017)
  • Author(s): Tsukao Y, Yamasaki M, Miyazaki Y, Makino T, Takahashi T, Kurokawa Y, Miyata H, Nakajima K, Takiguchi S, Mimori K, Mori M, Doki Y
  • Journal Title: Oncol Lett. Volume: 13(3) Pages: 1819-1825
  • DOI: 10.3892/ol.2017.5637.
  • Peer Reviewed / Open Access
• [Journal Article] The loss of CASP4 expression is associated with poor prognosis in esophageal squamous cell carcinoma (2017)
  • Author(s): Shibamoto M, Hirata H, Eguchi H, Sawada G, Sakai N, Kajiyama Y, Mimori K
  • Journal Title: Oncol Lett Volume: 13(3) Pages: 1761-1766
  • DOI: 10.3892/ol.2017.5646.
  • Peer Reviewed / Open Access
• [Journal Article] Altered Expression of Hippo Signaling Pathway Molecules in Intrahepatic Cholangiocarcinoma (2017)
  • Author(s): Sugimachi K, Nishio M, Aishima S, Kuroda Y, Iguchi T, Komatsu H, Hirata H, Sakimura S, Eguchi H, Bekki Y, Takenaka K, Maehara Y, Suzuki A, Mimori K
  • Journal Title: Oncology Volume: 93(1) Pages: 67-74
  • DOI: 10.1159/000463390.
  • Peer Reviewed / Open Access
• [Journal Article] Extraction of cell-free DNA from urine, using polylysine-coated silica particles. (2017)
  • Author(s): Takano S, Hu Q, Amamoto T, Refinetti P, Mimori K, Funatsu T, Kato M
  • Journal Title: Anal Bioanal Chem Volume: 409(16) Pages: :4021-4025
  • DOI: 10.1007/s00216-017-0345-3
  • Peer Reviewed / Open Access
• [Journal Article] MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. (2017)
  • Author(s): Otsubo K, Goto H, Nishio M, Kawamura K, Yanagi S, Nishie W, Sasaki T, Maehama T, Nishina H, Mimori K, Nakano T, Shimizu H, Mak TW, Nakao K, Nakanishi Y, Suzuki A
  • Journal Title: Oncogene. Volume: 36(29) Pages: 4201-4211
  • DOI: 10.1038/onc.2017.58.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Significance of FANCD Gene Expression and its Association with Tumor Progression in Hepatocellular Carcinoma. (2017)
  • Author(s): Komatsu H, Masuda T, Iguchi T, Nambara S, Sato K, Hu Q, Hirata H, Ito S, Eguchi H, Sugimachi K, Eguchi H, Doki Y, Mori M, Mimori K
  • Journal Title: Anticancer Res Volume: 37(3) Pages: 1083-1090
  • Peer Reviewed
• [Journal Article] Clinical Impact of Tumor-Infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma. (2017)
  • Author(s): Sudo T, Nishida R, Kawahara A, Saisho K, Mimori K, Yamada A, Mizoguchi A, Kadoya K, Matono S, Mori N, Tanaka T, Akagi Y
  • Journal Title: Ann Surg Oncol. Volume: 24(12) Pages: 3763-3770
  • DOI: 10.1245/s10434-017-5796-4.
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of ST6GALNAC1 is associated with esophageal squamous cell carcinoma development (2017)
  • Author(s): Iwaya T, Sawada G, Amano S, Kume K, Ito C, Endo F, Konosu M, Shioi Y, Akiyama Y, Takahara T, Otsuka K, Nitta H, Koeda K, Mizuno M, Nishizuka S, Sasaki A, Mimori K
  • Journal Title: Int J Oncol Volume: 50(2) Pages: 441-447
  • DOI: 10.3892/ijo.2016.3817.
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of CXCR7 Is a Novel Prognostic Indicator in Gastric Cancer. (2017)
  • Author(s): Nambara S, Iguchi T, Oki E, Tan P, Maehara Y, Mimori K
  • Journal Title: Dig Surg Volume: 34(4) Pages: 312-318
  • DOI: 10.1159/000452977.
  • Peer Reviewed / Open Access
• [Journal Article] The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers (2017)
  • Author(s): Kasagi Y, Oki E, Ando K, Ito S, Iguchi T, Sugiyama M, Nakashima Y, Ohgaki K, Saeki H, Mimori K, Maehara Y
  • Journal Title: Oncology. Volume: 92(1) Pages: 48-54
  • DOI: 10.1159/000452143.
  • Peer Reviewed / Open Access
• [Journal Article] Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma (2017)
  • Author(s): Komatsu H, Iguchi T, Masuda T, Hirata H, Ueda M, Kidogami S, Ogawa Y, Sato K, Hu Q, Nambara S, Saito T, Sakimura S, Uchi R, Ito S, Eguchi H, Sugimachi K, Eguchi H, Doki Y, Mori M, Mimori K
  • Journal Title: Ann Surg Oncol. Volume: 24(3) Pages: 850-859
  • DOI: 10.1245/s10434-016-5573-9.
  • Peer Reviewed / Open Access
• [Journal Article] As a Novel Prognostic Marker, Cysteine/histidine-rich 1 (CYHR1) is a Therapeutic Target in Patients with Esophageal Squamous Cell Carcinoma. (2017)
  • Author(s): Desaki R, Sawada G, Okumura H, Ikeda R, Tanabe K, Komatsu H, Mimori K, Mori M, Kita Y, Uchikado Y, Arigami T, Uenosono Y, Owaki T, Ishigami S, Natsugoe S
  • Journal Title: Ann Surg Oncol. Volume: 24(2) Pages: 586-593
  • DOI: 10.1245/s10434-015-5031-0.
  • Peer Reviewed / Open Access
• [Presentation] 大腸がんにおける進化機構のシフトによる腫瘍内多様性の創出 (2018)
  • Author(s): 三森功士
  • Organizer: 第14回日本消化管学会総会学術集会
• [Presentation] 大腸がんにおける新たな進化と選択圧について (2018)
  • Author(s): 三森功士
  • Organizer: 第2回消化器外科臨床応用をめざす研究交流会
  • Invited
• [Presentation] 大腸がんにおける新たな進化と多様性創出機構について (2017)
  • Author(s): 三森功士
  • Organizer: Translation Research Seminar
• [Presentation] がん転移再発の早期診断におけるctDNAの臨床的有用性について (2017)
  • Author(s): 三森功士
  • Organizer: JBICバイオ関連基盤技術研究会
• [Presentation] 薬物動態から見直す大腸がん化学療法 (2017)
  • Author(s): 三森功士
  • Organizer: 第28回日本消化器癌発生学会
  • Invited
• [Presentation] 消化器がん転移再発診断と治療評価法に関するctDNA解析の臨床的有用性と今後の課題 (2017)
  • Author(s): 三森功士
  • Organizer: 第55回日本癌治療学会学術集会
• [Presentation] 大腸発がんから進行がんにいたる過程のゲノムレベル進化について (2017)
  • Author(s): 三森功士
  • Organizer: 第3回がんゲノム・エピゲノムセミナー
• [Presentation] ctDNAにおいて突然変異の検出が可能な原発巣の特徴 (2017)
  • Author(s): 三森功士
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 消化器がん症例の様々な臨床的局面における血中ctDNA突然変異検出の意義 (2017)
  • Author(s): 三森功士
  • Organizer: 第26回日本がん転移学会
• [Presentation] 消化器癌におけるctDNA検出の臨床的意義と臨床応用にむけての提言 (2017)
  • Author(s): 三森功士
  • Organizer: 第72回日本消化器外科学会
• [Presentation] プロパゲルマニウム（SK-818）の骨髄由来細胞制御機構による癌転移巣増殖制御について (2017)
  • Author(s): 三森功士
  • Organizer: 第38回日本炎症・再生医学会
  • Invited
• [Presentation] 大腸がんの進化と転移再発を決める選択圧について (2017)
  • Author(s): 三森功士
  • Organizer: 昭和大学横浜北部病院2017年消化器センター軽井沢セミナー
  • Invited
• [Presentation] がん治療における革新的変化を踏まえた最先端技術，新たな開発戦略の現状と今後の方向性 (2017)
  • Author(s): 三森功士
  • Organizer: 第23回抗悪性腫瘍薬開発フォーラム