Driver and druggable oncogene aberrations in KRAS mutation-negative pancreatic ductal adenocarcinoma

• Project/Area Number: 26461039
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Ueno Hideki 国立研究開発法人国立がん研究センター, 中央病院, 医長 (10307522)
• Co-Investigator(Kenkyū-buntansha): 奥坂 拓志 国立研究開発法人国立がん研究センター, 中央病院, 科長 (70501849)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 膵がん / 遺伝子融合 / 治療標的 / KRAS遺伝子変異 / 癌 / 遺伝子 / トランスレーショナルリサーチ / KRAS / がん遺伝子 / 遺伝子変異

Outline of Final Research Achievements

Oncogenic mutations in the KRAS gene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without the KRAS mutation. Whole exome and transcriptome sequencing was performed on four cases of KRAS mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases. One case harbored an oncogenic DCTN1 (dynactin 1)-ALK fusion. The fusion gene enabled IL-3-independent growth of Ba/F3 cells and rendered them susceptible to the ALK tyrosine kinase inhibitors crizotinib and alectinib. Another case harbored an oncogenic RRAS mutation that activated the GTPase of the RRAS protein. The results suggest that rare oncogenic aberrations, such as the ALK fusion and RRAS mutation, drive pancreatic carcinogenesis independent of the KRAS mutation and can be a therapeutic target.

Research Products

• [Journal Article] An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma (2017)
  • Author(s): Shimada Y, Kohno T, Ueno H, Ino Y, Hayashi H, Nakaoku T, Sakamoto Y, Kondo S, Morizane C, Shimada K, Okusaka T, Hiraoka N.
  • Journal Title: Oncologist Volume: 22 Issue: 2 Pages: 158-164
  • DOI: 10.1634/theoncologist.2016-0194
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer. (2017)
  • Author(s): Hayashi H, Kohno T, Ueno H, Hiraoka N, Kondo S, Saito M, Shimada Y, Ichikawa H, Kato M, Shibata T, Morizane C, Sakamoto Y, Shimada K, Komatsu Y, Sakamoto N, Okusaka T
  • Journal Title: Pancreas Volume: 46 Issue: 3 Pages: 335-340
  • DOI: 10.1097/mpa.0000000000000760
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 【膵・胆道癌診療の新時代へ-診断と治療の新た な展開-】 次世代シークエンサーを用いた膵癌遺伝子プロファイリング (2015)
  • Author(s): 林秀幸, 上野秀樹, 河野隆志
  • Journal Title: 胆と膵 Volume: 36 Pages: 131-134
• [Journal Article] 【膵・胆道癌診療の新時代へ-診断と治療の新たな展開-】 次世代シークエンサーを用いた膵癌遺伝子プロファイリング (2015)
  • Author(s): 林秀幸, 上野秀樹, 河野隆志
  • Journal Title: 胆と膵 Volume: 36 Pages: 131-134
• [Presentation] Gene mutation profile of pancreatic cancer obtained using targeted deep sequencing and its association with prognosis (2014)
  • Author(s): Hayashi H, Ueno H, Sakamoto Y, Kondo S, Morizane C, Saito M, Shimada K, Ichikawa H, Hiraoka N, Kohno T, OKusaka T
  • Organizer: ESMO (EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY) 2014 Congress
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2014-09-26 – 2014-09-30
• [Presentation] Gene aberration profile of pancreatic cancer in Japanese patients (2014)
  • Author(s): Hayashi H, Ueno H, Sakamoto Y, Kondo S, Morizane C, Shimada K, Ichikawa H, Hiraoka N, Kohno T, OKusaka T
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17 – 2014-07-19