An Oncogenic Fusion and an Mutation in Mutation-Negative Pancreatic Ductal Adenocarcinoma.

PURPOSE

Oncogenic mutations in the 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 mutation.

METHODS

Whole-exome and transcriptome sequencing was performed on four cases of mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases.

RESULTS

One case harbored an oncogenic - fusion. The fusion gene enabled interleukin-3-independent growth of Ba/F3 cells and rendered them susceptible to the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. The structure of the breakpoint junction indicated that the fusion was generated by nonhomologous end joining between a segment of exon DNA and a segment of intron DNA, resulting in the generation of a cryptic splicing site. Another case harbored an oncogenic mutation that activated the GTPase of the RRAS protein.

CONCLUSION

Rare oncogenic aberrations, such as the fusion and mutation, may drive pancreatic carcinogenesis independent of the mutation. 2017;22:158-164 The oncogenic - fusion and the mutation were associated with the development of pancreatic ductal adenocarcinoma (PDAC) in the absence of the mutation. Constitutional activation of - fusion protein was suppressed by the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. Thus, a small subset of PDAC patients might benefit from therapy using these inhibitors.