Genetic alterations in early-onset pancreatic cancer

• Project/Area Number: 17K09451
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Sasajima Junpei 旭川医科大学, 医学部, 客員講師 (80451467)
• Co-Investigator(Kenkyū-buntansha): 水上 裕輔 医療法人徳洲会札幌東徳洲会病院医学研究所, がん研究部, 部門長 (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, 臨床生体情報解析部, 部門長 (40742648) ; 田中 宏樹 旭川医科大学, 医学部, 助教 (70596155)
• Project Period (FY): 2017-04-01 – 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 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / 感受性遺伝子 / 若年発症 / コピー数変異 / 体細胞変異解析 / 次世代シーケンサー / コピー数多型 / メチル化解析 / 癌 / 遺伝子 / 細胞・組織 / 臨床

Outline of Final Research Achievements

This study aimed to examine novel genetic alterations that are useful for predicting the onset of pancreatic cancer. Fifty-two early-onset Japanese pancreatic cancer patients who developed the disease under the age of 50 were enrolled, and exome sequencing was performed to identify pathogenic germline variants. Three potential susceptibility genes were found. A reanalysis of publicly available somatic mutation data, including 109 cases from UT Southwestern Medical Center, identified a significant number of copy number mutations in young-onset cases. Using tumor-normal tissue pair from our Japanese cohort, we validated the abnormality was more frequently observed in the early onset cases relative to average aged patients. Our findings will support the algorithm's basis to predict subjects who are at high risk of developing pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

膵癌の発症年齢中央値は70歳台前半であるが、30-40歳台の若年発症を稀に見る。これまでに、BRCA1/2, CDKN2A, STK11など、複数の膵癌感受性遺伝子が一部同定されており、ゲノム異常の全貌を明らかにすることは、膵発癌の高危険群を特定する重要な情報と考えられる。自験例から得た新規の膵癌感受性遺伝子に関わる情報、及び既存データベースの再解析結果を基に、膵癌発症の高危険群を絞り込むためのアルゴリズムを構築し、その臨床的な意義を今後検証する。

Research Products

• [Journal Article] Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes (2020)
  • Author(s): Aoki Yasutaka、Mizuma Masamichi、Hata Tatsuo、Aoki Takeshi、Omori Yuko、Ono Yusuke、Mizukami Yusuke、Unno Michiaki、Furukawa Toru
  • Journal Title: The Journal of Pathology Volume: 251 Issue: 1 Pages: 38-48
  • DOI: 10.1002/path.5398
  • Peer Reviewed / Open Access
• [Journal Article] Comparative genome-wide analysis of gastric adenocarcinomas with hyperplastic polyp components (2019)
  • Author(s): Yoshiyasu Takayama, Yusuke Ono, Yusuke Mizukami, Hideaki Itoh, Nozomi Nakajima, Hideo Arai, Shinya Tanaka, Sumihito Nobusawa, Hideaki Yokoo, Yasuhiro Onozato
  • Journal Title: Virchows Arch Volume: 475 Issue: 3 Pages: 383-389
  • DOI: 10.1007/s00428-019-02592-y
  • Peer Reviewed
• [Journal Article] Clinical course of conservative management for isolated superior mesenteric arterial dissection (2019)
  • Author(s): Sosogi Sho、Sato Ryu、Wada Reona、Saito Hiroya、Takauji Shuhei、Sakamoto Jun、Kimura Keisuke、 Karasaki Hidenori、Mizukami Yusuke、Ohta Tomoyuki
  • Journal Title: European Journal of Radiology Open Volume: 6 Pages: 192-197
  • DOI: 10.1016/j.ejro.2019.05.004
  • Peer Reviewed / Open Access
• [Journal Article] Metachronous intraductal papillary mucinous neoplasms disseminate via the pancreatic duct following resection (2019)
  • Author(s): Nagai Kazumasa、Mizukami Yusuke、Omori Yuko、Kin Toshifumi、Yane Kei、Takahashi Kuniyuki、Ono Yusuke、Sugitani Ayumu、Karasaki Hidenori、Shinohara Toshiya、Furukawa Toru、Hayashi Tsuyoshi、Okumura Toshikatsu、Maguchi Hiroyuki、Katanuma Akio
  • Journal Title: Modern Pathology Volume: 33 Issue: 5 Pages: 971-980
  • DOI: 10.1038/s41379-019-0405-7
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB. (2019)
  • Author(s): Kawabata H, Miyazawa Y, Sato H, Okada T, Hayashi A, Iwama T, Fujibayashi S, Goto T, Sasajima J, Takauji S, Fujiya M, Torimoto Y, Tanino M, Omori Y, Ono Y, Karasaki H, Mizukami Y, Okumura T.
  • Journal Title: Endosc Int Open. Volume: 7(12) Issue: 12 Pages: E1768-E1772
  • DOI: 10.1055/a-1034-7700
  • Peer Reviewed / Open Access
• [Journal Article] Lymph Node Metastasis From Gastroesophageal Cancer Successfully Treated by Nivolumab: A Case Report of a Young Patient. (2019)
  • Author(s): Kashima S, Tanabe H, Tanino M, Kobayashi Y, Murakami Y, Iwama T, Sasaki T, Kunogi T, Takahashi K, Ando K, Ueno N, Moriichi K, Fukudo M, Tasaki Y, Hosokawa M, Mizukami Y, Fujiya M, Okumura T.
  • Journal Title: Front Oncol. Volume: 9 Pages: 1375-1375
  • DOI: 10.3389/fonc.2019.01375
  • Peer Reviewed / Open Access
• [Journal Article] ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics and immune evasion of pancreatic cancer (2019)
  • Author(s): Hashimoto, S*., Furukawa, S*., Hashimoto, A*., Tsutaho, A., Fukao, A., Sakamura, Y., Parajuli, G., Onodera, Y., Otsuka, Y., Handa, H., Oikawa, T., Hata, S., Nishikawa Y., Mizukami, Y., Kodama, Y., Murakami M., Fujiwara, T., Hirano, S., and Sabe, H. (*Equally contributed)
  • Journal Title: Proceedings of the National Academy of the Sciences of the United States of America Volume: 116 Issue: 35 Pages: 17450-17459
  • DOI: 10.1073/pnas.1901765116
  • Peer Reviewed / Open Access
• [Journal Article] 特集 肝胆膵領域とゲノム医療新時代-遺伝子パネルがやってきた！- IPMNのゲノム解析. (2019)
  • Author(s): 林 明宏、水上裕輔、佐藤裕基、河端秀賢、岡田哲弘、後藤拓磨、河本 徹、小野裕介、唐崎秀則、奥村 利勝
  • Journal Title: 肝・胆・膵 Volume: 79 Pages: 1125-1133
• [Presentation] リキッドバイオプシーによる膵癌診断 Liquid biopsy in pancreatic tumors; Challenges for early detection and surveillance. (2019)
  • Author(s): 水上裕輔、小野裕介、奥村利勝
  • Organizer: 第78回日本癌学会学術総会 Symposium22; Liquid biopsy
  • Invited
• [Presentation] デジタルPCRを用いた血漿遊離核酸からの膵腫瘍の検出－早期診断への活用に向けて－ Screening of mutations in circulating cellfree DNA for early-stage diagnosis and surveillance of pancreatic tumors. (2019)
  • Author(s): 小野裕介、唐崎秀則、水上裕輔.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] デジタルPCRによるBRAF遺伝子変異検査は甲状腺乳頭癌のFNA正診率を向上させる BRAF mutation testing by dPCR improves the diagnosis accuracy of FNA for the papillary thyroid carcinoma (2019)
  • Author(s): 北崎アリサ、駒林優樹、小野裕介、木村太一、田中伸哉、長嶋和郎、水上裕輔.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] IPMN関連膵癌の分子基盤と進展経路 (2019)
  • Author(s): 水上裕輔、大森優子、唐崎秀則
  • Organizer: 第50回日本膵臓学会大会 パネルディスカッション
• [Presentation] 血漿遊離核酸を用いた膵腫瘍診断 (2019)
  • Author(s): 岡田哲弘、水上裕輔、河本 徹、林 明宏、佐藤裕基、河端秀賢、後藤拓磨、笹島順平、小泉一也、高橋邦幸、岩野博俊、浅原新吾、桑谷 将城、唐崎秀則、奥村利勝
  • Organizer: 第50回日本膵臓学会大会
• [Presentation] Capturing Pancreatic Tumor-derived Mutations from Fine Needle Aspiration Using Digital PCR. (2019)
  • Author(s): Ono Y, Hayashi A, Wada R, Suzuki M, Maeda C, Okada T, Sato H, Kawabata H, Goto T, Karasaki H, Mizukami Y, Okumura T.
  • Organizer: The 50th Anniversary Joint Meeting of APA & JPS
  • Int'l Joint Research
• [Presentation] The Temporal Order of KRAS and GNAS Mutations in Intraductal Papillary Mucinous Neoplasms of the Pancreas and Evolution to Invasive Carcinoma. (2019)
  • Author(s): Mizukami Y, Karasaki H, Ono Y, Omori Y, Hayashi A, Tachibana S, Sugiyama Y, Sato H, Kawabata H, Goto T, Fujiya M, Takahashi K, Katanuma A, Maguchi H, Furukawa T, Okumura T.
  • Organizer: The 50th Anniversary Joint Meeting of APA & JPS
  • Int'l Joint Research
• [Presentation] PATHWAYS OF PROGRESSION FROM INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM AND THE GENETIC DIVERSITY OF ASSOCIATED ORGAN FIELD. (2019)
  • Author(s): Mizukami Y, Omori Y, Ono Y, Karasaki H, Tanino M, Yamaguchi H, Furukawa T, Maguchi H, Tanaka S, Okumura T
  • Organizer: DDW2019米国消化器病週間
  • Int'l Joint Research
• [Presentation] ABNORMAL ACTIVATION OF HNRNPA0 INHIBITS CANCER CELL APOPTOSIS AND PROMOTES EXCESSIVE MITOSIS IN CANCER CELLS. (2019)
  • Author(s): Konishi H, Fujiya M, Kita A, Tanaka H, Kashima S, Sakatani A, Dokoshi T, Ando K, Ueno N, Moriichi K, Iwama T, Takahashi K, Murakami Y, Ikuta K, Mizukami Y, Goto T, Okumura T.
  • Organizer: DDW2019米国消化器病週間
  • Int'l Joint Research