Distribution and clonality of multiple intraductal neoplasms of the pancreas evaluated by morphology

• Project/Area Number: 20K09070
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital
• Principal Investigator: Karasaki Hidenori 医療法人徳洲会札幌東徳洲会病院医学研究所, がん生物研究部, 客員研究員 (50374806)
• Co-Investigator(Kenkyū-buntansha): 水上 裕輔 旭川医科大学, 医学部, 教授 (30400089) ; 小野 裕介 医療法人徳洲会札幌東徳洲会病院医学研究所, ゲノム診断研究部, 部門長 (40742648)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 背景膵 / 膵管内病変 / clonality / 正常膵管 / 膵発癌 / 領域発癌 / KRAS / 指標病変 / 低異型度病変 / field defect / heterogeneity / 液体生検 / 膵発癌素地 / 膵癌 / Clonarity

Outline of Research at the Start

本研究では、通常型膵癌の切除材料を用いて背景膵の膵管内病変の形態的特徴と膵内分布、遺伝子変異を詳細に解析し、術後再発との関連づけ を試みる。さらに、膵癌の初期発生に迫るため、膵腺房―導管異形成（Acinar-to-ductal metaplasia; ADM）や異型度の低い膵上皮内病変（Pancreatic intraepithelial neoplasia; PanIN）の存在にも着目する。背景膵に分布する膵管内病変の分布とゲノム異常をマーカーとしてこれらのclonalityを明らかにすることによって、術後再発や生命予後に有効な指標を得ることを目指す。

Outline of Final Research Achievements

The liquid biopsy, promising clinical application for early detection of pancreatic neoplasms consist of many molecular alterations about not only the index tumor but also the background. For better understanding of the genetic alterations occurring throughout the pancreas, mutation analysis of multiple sites, including normal pancreatic ducts, in two cases with high-grade IPMN and double pancreatic cancer as index lesions, respectively. Approximately 40% of the patients had some kind of gene mutation. The majority of these mutations were low-grade intraductal lesions, but mutations were also found in some normal pancreatic ducts. There was no significant difference in the number of samples examined between the two cases, the distribution of grades, and the rate of concordance in KRAS mutation type between index lesions and background pancreatic sites, but individual differences were observed in the number of KRAS mutations.

Academic Significance and Societal Importance of the Research Achievements

難治癌である膵癌の早期発見のために液体生検の臨床応用が期待されている。その解析資料として血液、十二指腸液、膵液などが検討されているが、いずれであっても指標病変だけではなく、背景に起こっている様々な分子情報が含まれることになる。これらの適切な解釈なしに液体生検の臨床応用はありえないが、背景膵の分子変化や、指標病変との関連の詳細は不明な点が多い。本研究は少数例ではあるが正常膵管も含め背景膵の多数箇所と指標病変の複数箇所の変異解析を行い、症例間で共通している、あるいは個体間で異なる変化を模索した。本研究の結果を基に多種類の膵腫瘍の背景情報を類型化することで液体生検の臨床応用に寄与しうる。

Research Products

• [Journal Article] A case of incipient pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm, confirmed by multiregion sequencing analysis (2022)
  • Author(s): 佐藤 允洋、唐崎 秀則、富永 素矢、坂本 淳、木村 圭介、太田 智之、田中 伸哉、水上 裕輔
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 119 Issue: 4 Pages: 368-376
  • DOI: 10.11405/nisshoshi.119.368
  • ISSN: 0446-6586, 1349-7693
  • Year and Date: 2022-04-10
• [Journal Article] Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway (2022)
  • Author(s): Kawabata Hidemasa、Ono Yusuke、Tamamura Nobue、Oyama Kyohei、Ueda Jun、Sato Hiroki、Takahashi Kenji、Taniue Kenzui、Okada Tetsuhiro、Fujibayashi Syugo、Hayashi Akihiro、ほか
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 3 Pages: 208-220
  • DOI: 10.1007/s00535-021-01846-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictors of Long-Term Survival in Pancreatic Ductal Adenocarcinoma after Pancreatectomy: TP53 and SMAD4 Mutation Scoring in Combination with CA19-9 (2022)
  • Author(s): Ono M, Ono Y, Nakamura T, Tsuchikawa T, Kuraya T, Kuwabara S, Nakanishi Y, Asano T, Matsui A, Tanaka K, Ebihara Y, Kurashima Y, Noji T, Murakami S, Shichinohe T, Mitsuhashi T, Omori Y, Furukawa T, Taniue K, Suzuki M, Sugitani A, Karasaki H, Mizukami Y, Hirano S.
  • Journal Title: Annals of Surgical Oncology Volume: 29 Issue: 8 Pages: 5007-5019
  • DOI: 10.1245/s10434-022-11630-0
  • Peer Reviewed
• [Journal Article] Distinct effects of TU-100 (daikenchuto) on long-lasting dysbiosis in the small intestine in patients with colorectal cancer and inflammatory bowel disease (2022)
  • Author(s): Kono T, Maejima T, Ono Y, Ito T, Furukawa S, Nishiyama M, Yamamoto M, Sugitani A, Karasaki H, Mizukami Y, Maemoto A.
  • Journal Title: Gene Volume: 820 Pages: 146266-146266
  • DOI: 10.1016/j.gene.2022.146266
  • Peer Reviewed
• [Journal Article] Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS-mutant and GNAS-wild-type Intraductal Papillary Mucinous Neoplasms of the Pancreas (2021)
  • Author(s): Omori Yuko、Ono Yusuke、Morikawa Takanori、Motoi Fuyuhiko、Higuchi Ryota、Yamamoto Masakazu、Hayakawa Yuko、Karasaki Hidenori、Mizukami Yusuke、Unno Michiaki、Furukawa Toru
  • Journal Title: Annals of Surgery Volume: Publish Ahead of Print Issue: 2 Pages: e384-e395
  • DOI: 10.1097/sla.0000000000004842
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathways for the development of multiple epithelial types of intraductal papillary mucinous neoplasm of the pancreas (2021)
  • Author(s): Kobayashi Toshikazu、Omori Yuko、Ono Yusuke、Karasaki Hidenori、Mizukami Yusuke、Makino Naohiko、Motoi Fuyuhiko、Unno Michiaki、Ueno Yoshiyuki、Furukawa Toru
  • Journal Title: Journal of Gastroenterology Volume: Online ahead of print Issue: 6 Pages: 581-592
  • DOI: 10.1007/s00535-021-01783-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic Tracing of Clonal Expansion and Progression of Pancreatic Ductal Adenocarcinoma: A Case Report and Multi-Region Sequencing Analysis (2020)
  • Author(s): Tachibana Shion、Mizukami Yusuke、Ono Yusuke、Sugiyama Yuya、Okada Tetsuhiro、Kitazaki Arisa、Sasajima Junpei、Tominaga Motoya、Sakamoto Jun、Kimura Keisuke、Omori Yuko、Furukawa Toru、Kimura Taichi、Tanaka Shinya、Nagashima Kazuo、Karasaki Hidenori、Ohta Tomoyuki、Okumura Toshikatsu
  • Journal Title: Frontiers in Oncology Volume: 10 Pages: 1-8
  • DOI: 10.3389/fonc.2020.00728
  • Peer Reviewed / Open Access
• [Journal Article] How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression. (2020)
  • Author(s): Omori Y, Ono Y, Kobayashi T, Motoi F, Karasaki H, Mizukami Y, Makino N, Ueno Y, Unno M, Furukawa T.
  • Journal Title: Virchows Archiv Volume: - Issue: 1 Pages: 1-11
  • DOI: 10.1007/s00428-020-02806-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 膵癌の初期発生とリキッドバイオプシーによる分子診断 (2020)
  • Author(s): 岡田哲弘 水上裕輔 林明宏 河端秀賢 佐藤裕基 河本徹 後藤拓磨 谷上賢端 小野裕介 唐崎秀則 奥村利勝
  • Journal Title: 膵臓 Volume: 35 Pages: 302-312
  • NAID: 130007893498
  • Peer Reviewed
• [Presentation] STK11 plays a canonical role in malignant progression of a subset of KRAS-mutant IPMNs. (2020)
  • Author(s): 大森優子、小野裕介、森川孝則、元井冬彦、樋口亮太、山本雅一、唐崎秀則、水上裕輔、海野倫明、古川 徹．
  • Organizer: 第109回日本病理学会総会
• [Presentation] FEASIBILITY OF DIGITAL PCR-BASED QUANTIFICATION AND MUTATION ANALYSIS OF PLASMA CELL-FREE DNA FOR DIAGNOSIS AND SURVEILLANCE OF EARLY-STAGE PANCREATIC TUMORS. (2020)
  • Author(s): Okada T, Mizukami Y, Koizumi K, Takahashi K, Iwano H, Asahara S, Kuwatani M, Kawamoto T, Sato H, Hayashi A, Kawabata H, Goto T, Sasajima J, Fujiya M, Ono Y, Karasaki H, Okumura T.
  • Organizer: DDW2020
  • Int'l Joint Research
• [Presentation] STK11 Plays a Canonical Role in Malignant Progression of a Subset of KRAS-mutant Intraductal Papillary Mucinous Neoplasms. (2020)
  • Author(s): Omori Y, Ono Y, Morikawa T, Motoi F, Higuchi R, Yamamoto M, Karasaki H, Mizukami Y, Unno M, Furukawa T.
  • Organizer: 109th USCAP Annual Meeting
  • Int'l Joint Research