Establishment of immunohistochemical molecular subtyping based on gene expression profiling and morphology of pancreatic ductal carcinomas

• Project/Area Number: 25460449
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hokkaido University
• Principal Investigator: Mitsuhashi Tomoko 北海道大学, 大学病院, 准教授 (60348208)
• Co-Investigator(Kenkyū-buntansha): 畑中 豊 北海道大学, 大学病院, 特任講師 (30589924)
• Co-Investigator(Renkei-kenkyūsha): MATSUNO Yoshihiro 北海道大学, 大学病院, 教授 (00199829) ; HIRANO Satoshi 北海道大学, 医学(系)研究科(研究院), 教授 (50322813)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 分子サブタイピング / 膵癌 / 浸潤性膵管癌 / 治療効果予測

Outline of Final Research Achievements

In this study, we tried to establish the immunohistochemical (IHC) molecular subtyping that might be introduced to our daily practice on diagnostic surgical pathoplogy, based on the gene expression profiles of pancreatic ductal carcinomas (PDACs). Tissue microarray blocks constructed by 155 cases of PDACs were used. IHC analysis was done by routine procedures. Gene expression profiling analysis was done using the GeneChip microarray system. Thirteen signature molecules forming molecular subtyping of PDACs were analyzed. The low expression group for TFF1 and the high expression group for either CAV1，S100A2 or NT5E showed a significant shortened overall survival. The gene expression profiling analysis for PDAC cases subtyped by IHC markers revealed that these IHC molecular subtypes were adequate. According to the above results, IHC markers that surrogate subtypes based on the gene expression profiles will enable the molecular subtyping of PDACs.

Research Products

• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • Author(s): Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: J Clin Pathol Volume: in press Issue: 7 Pages: 593-599
  • DOI: 10.1136/jclinpath-2015-203115
  • Peer Reviewed
• [Journal Article] Stromal Palladin Expression Is an Independent Prognostic Factor in Pancreatic Ductal Adenocarcinoma (2016)
  • Author(s): Sato D, Tsuchikawa T, Mitsuhashi T, Hatanaka Y, Marukawa K, Morooka A, Nakamura T, Shichinohe T, Matsuno Y, Hirano S
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152523-e0152523
  • DOI: 10.1371/journal.pone.0152523
  • NAID: 120005757988
  • Peer Reviewed / Open Access
• [Journal Article] The impact of margin status determined by the one-millimeter rule on tumor recurrence and survival following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. (2016)
  • Author(s): Nitta T, Nakamura T, Mitsuhashi T, Asano T, Okamura K, Tsuchikawa T, Tamoto E, Murakami S, Noji T, Kurashima Y, Ebihara Y, Nakanishi Y, Shichinohe T, Hirano S.
  • Journal Title: Surg Today Volume: Epub ahead of print
  • NAID: 120006415997
  • Peer Reviewed
• [Journal Article] Usefulness of the octreotide test in Japanese patients for predicting the presence/absence of somatostatin receptor 2 expression in insulinomas (2016)
  • Author(s): Nakamura A, Mitsuhashi T, Takano Y, Miyoshi H, Kameda H, Nomoto H, Nagai S, Hatanaka Y, Shimizu C, Terauchi Y, Atsumi T.
  • Journal Title: Endocrine Journal Volume: 63 Issue: 2 Pages: 135-142
  • DOI: 10.1507/endocrj.EJ15-0371
  • NAID: 130005127186
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Effect of a stylet on histological specimen in endoscopic ultrasound-guided fine needle tissue acquisition using 22-gauge needles: A multicenter prospective randomized controlled trial. (2015)
  • Author(s): Abe Y, Kawakami H, Oba K, Hayashi T, Yasuda I, Mukai T, Isayama H, Ishiwatari H, Doi S, Nakashima M, Yamamoto N, Kuwatani M, Mitsuhashi T, Hasegawa T, Hirose Y, Yamada T, Tanaka M, Sakamoto N, for the Japan EUS-FNA stylet Study Group
  • Journal Title: Gastrointest Endosc Volume: 82 Issue: 5 Pages: 837-844
  • DOI: 10.1016/j.gie.2015.03.1898
  • Peer Reviewed
• [Journal Article] Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma. (2015)
  • Author(s): Tsunematsu S, Chuma M, Kamiyama T, Miyamoto N, Yabusaki S, Hatanaka K, Mitsuhashi T, Kamachi H, Yokoo H, Kakisaka T, Tsuruga Y, Orimo T, Wakayama K, Ito J, Sato F, Terashita K, Nakai M, Tsukuda Y, Sho T, Suda G, Morikawa K, Natsuizaka M, Nakanishi M, Ogawa K, Taketomi A, Matsuno Y, Sakamoto N.
  • Journal Title: Abdom Imaging Volume: in press
  • Peer Reviewed
• [Journal Article] Immunohistochemical analysis of cancer stem cell markers in pancreatic adenocarcinoma patients after neoadjuvant chemoradiotherapy (2014)
  • Author(s): Mizukami T, Kamachi H, Mitsuhashi T, Tsuruga Y, Hatanaka Y, Kamiyama T, Matsuno Y, Taketomi A.
  • Journal Title: BMC Cancer Volume: 14 Issue: 1 Pages: 687-687
  • DOI: 10.1186/1471-2407-14-687
  • NAID: 120005496508
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray. (2014)
  • Author(s): Nitta T, Mitsuhashi T, Hatanaka Y, Miyamoto M, Oba K, Tsuchikawa T, Suzuki Y, Hatanaka KC, Hirano S, Matsuno Y.
  • Journal Title: Br J Cancer Volume: 111 Issue: 7 Pages: 1363-1372
  • DOI: 10.1038/bjc.2014.415
  • NAID: 120005656331
  • Peer Reviewed / Open Access
• [Journal Article] CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using endoscopic ultrasound-guided fine-needle aspiration and next-generation deep sequencing. (2014)
  • Author(s): Kubota Y, Kawakami H, Natsuizaka M, Kawakubo K, Marukawa K, Kudo T, Abe Y, Kubo K, Kuwatani M, Hatanaka Y, Mitsuhashi T, Matsuno Y, Sakamoto N.
  • Journal Title: J Gastroenterol. Volume: in press Issue: 2 Pages: 203-210
  • DOI: 10.1007/s00535-014-0954-y
  • NAID: 120005693897
  • Peer Reviewed
• [Journal Article] CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using endoscopic ultrasound-guided fine-needle aspiration and next-generation deep sequencing. (2014)
  • Author(s): Kubota Y, Kawakami H, Natsuizaka M, Kawakubo K, Marukawa K, Kudo T, Abe Y, Kubo K, Kuwatani M, Hatanaka Y, Mitsuhashi T, Matsuno Y, Sakamoto N
  • Journal Title: J Gastroenterol Volume: in press
  • NAID: 120005693897
  • Peer Reviewed
• [Journal Article] Epstein-barr virus-associated smooth muscle tumors after bone marrow transplantation. (2014)
  • Author(s): Hayase E, Fujimoto K, Mitsuhashi T, Hatanaka Y, Yoshida M, Takemura R, Iwasaki J, Shiratori S, Sugita J, Kondo T, Tanaka J, Imamura M, Matsuno Y, Teshima T
  • Journal Title: Transplantation Volume: 97 Issue: 1 Pages: e1-e5
  • DOI: 10.1097/01.tp.0000437912.60638.23
  • Peer Reviewed
• [Journal Article] 体外式超音波検査による肝外胆管癌の右肝動脈および神経周囲浸潤診断能の検討． (2014)
  • Author(s): 佐藤 恵美，西田 睦，工藤 悠輔，井上 真美子，表原 里実，平野 聡，河上 洋，工藤 大樹，三橋 智子，仲 知保
  • Journal Title: 超音波検査技術 Volume: 39 Pages: 22-30
  • NAID: 130004950063
  • Peer Reviewed
• [Journal Article] Pancreatic ductal adenocarcinomas with multiple large cystic structures: A clinicopathologic and immunohistochemical study of seven cases. (2013)
  • Author(s): Nitta T, Mitsuhashi T, Hatanaka Y, Hirano S, Matsuno Y
  • Journal Title: Pancreatology Volume: 13 Issue: 4 Pages: 401-8
  • DOI: 10.1016/j.pan.2013.05.004
  • NAID: 120005946788
  • Peer Reviewed
• [Journal Article] An intraductal papillary neoplasm of the bile duct mimicking a hemorrhagic hepatic cyst: a case report. (2013)
  • Author(s): Kakisaka T, Kamiyama T, Yokoo H, Nakanishi K, Wakayama K, Tsuruga Y, Kamachi H, Mitsuhashi T, Taketomi A
  • Journal Title: World J Surg Oncol Volume: 11 Issue: 1 Pages: 1-5
  • DOI: 10.1186/1477-7819-11-111
  • NAID: 120005311818
  • Peer Reviewed
• [Journal Article] 超音波検査による膵管癌の上腸間膜動脈周囲神経叢浸潤の診断能の検討． (2013)
  • Author(s): 工藤 悠輔，西田 睦，佐藤 恵美，井上 真美子，表原 里実，堀江 達則，岩井 孝仁，和田 妙子，三橋 智子，清水 力
  • Journal Title: 超音波検査技術 Volume: 38 Pages: 359-67
  • NAID: 130005480678
  • Peer Reviewed
• [Journal Article] 胆膵領域の病理診断に有用な免疫染色 (2013)
  • Author(s): 三橋 智子
  • Journal Title: 病理と臨床 Volume: 31 Pages: 356-62
• [Presentation] 膵管内乳頭粘液性腫瘍の膵液細胞診について (2016)
  • Author(s): 三橋 智子
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] 膵管癌におけるNT5E発現における臨床病理学的検討 (2016)
  • Author(s): 諸岡 亜早美，畑中 豊，丸川 活司，上野 峰，佐藤 大介，平野 裕子，奥村 麻美，清水 知浩，畑中 佳奈子，三橋 智子，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Presentation] 低分化肝外胆管癌における臨床病理学的因子の検討 (2016)
  • Author(s): 上野 峰，三橋 智子，畑中 豊，岡村 圭祐，平野 聡，松野 吉宏
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Presentation] Clinicopathological significance of MUC13 expression in pancreatic ductal adenocarcinoma (PDAC); the positive prognostic marker and possible candidate for molecular targeted therapy. (2016)
  • Author(s): Marukawa K, Mitsuhashi T, Hatanaka Y, Morooka A, Sato D, Nitta T, Nakamura T, Hirano S, Matsuno Y.
  • Organizer: Annual Meeting, United States and Canadian Academy of Pathology
  • Place of Presentation: Washington State Convention Center, Seattle, USA
  • Year and Date: 2016-03-12
• [Presentation] 消化器領域の神経内分泌腫瘍 (2015)
  • Author(s): 三橋 智子
  • Organizer: 第56回日本臨床細胞学会総会（春期大会）
  • Place of Presentation: くにびきメッセ・松江テルサ（島根県松江市）
  • Year and Date: 2015-06-12
  • Invited
• [Presentation] 胆道腺扁平上皮癌の診断におけるp40、p63免疫染色の有用性 (2015)
  • Author(s): 佐藤大介、三橋智子、畑中豊、岡村圭祐、平野聡、松野吉宏
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] 平坦-低乳頭状 intra ductal papillary mucinous neoplasm(IPMN)の病理学的検討 (2014)
  • Author(s): 佐藤大介、三橋智子、畑中豊、中村透、平野聡、松野吉宏
  • Organizer: 第45回日本膵臓学会大会
  • Place of Presentation: 北九州国際会議場（北九州市）
  • Year and Date: 2014-07-11 – 2014-07-12
• [Presentation] 胆道乳頭状腫瘍におけるIntra ductal papillary neoplasm of bile duct(IPNB)，Intracystic papillary neoplasm(ICPN)診断基準の検討 (2014)
  • Author(s): 佐藤大介、三橋智子、畑中豊、中西喜嗣、平野聡、松野吉宏
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 平坦-低乳頭状 intra ductal papillary mucinous neoplasm(IPMN)の病理学的検討 (2014)
  • Author(s): 佐藤 大介，三橋 智子，畑中 豊，中村 透，平野 聡，松野 吉宏
  • Organizer: 第45回 日本膵臓学会大会
  • Place of Presentation: 北九州国際会議場（北九州市）
• [Presentation] 胆道乳頭状腫瘍におけるIPNB，ICPNの診断基準の検討 (2014)
  • Author(s): 佐藤 大介，三橋 智子，畑中 豊，中西 喜嗣，平野 聡，松野 吉宏
  • Organizer: 第103回 日本病理学会総会
  • Place of Presentation: 広島国際会議場（広島市）
• [Presentation] Diagnostic criteria for Intraductal (intracystic) papillary neoplasm of the bile duct (IPNB) and the gallbladder (ICPN): Histological and immunohistochemical (IHC) evaluation of 50 cases. (2014)
  • Author(s): Sato D, Mitsuhashi T, Hatanaka Y, Nakanishi Y, Hirano S, Matsuno Y
  • Organizer: 103rd United States & Canadian Academy of Pathology Annual Meeting
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
• [Presentation] 膵NET-病理・細胞診断の実際と新たな評価項目 (2013)
  • Author(s): 三橋 智子
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Book] 膵癌 Ⅱ．各論 上皮性腫瘍 嚢胞性膵腫瘍 膵粘液性嚢胞腫瘍（MCN）MCNの発生機序 日本臨牀 73巻 増刊号3 (2015)
  • Author(s): 三橋 智子
  • Publisher: 日本臨牀社
• [Book] 腫瘍病理鑑別診断アトラス（第1部 検鏡前の確認事項 Ⅱ．病理標本の取り扱い方 2. 手術切除標本） (2015)
  • Author(s): 三橋 智子
  • Publisher: 文光堂
• [Book] 腫瘍病理鑑別診断アトラス 胆道癌・膵癌 (2015)
  • Author(s): 三橋 智子
  • Publisher: 文光堂