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

2016 Fiscal Year Final Research Report

• 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)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 膵がん / 遺伝子融合 / 治療標的 / KRAS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.

Free Research Field

がん遺伝学