Aims The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC.
Methods Whole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated.
Results 400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC.
Conclusion NTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.
- pancreatic neoplasms
Data availability statement
No data are available.
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Handling editor Runjan Chetty.
Contributors Study concept and design: MJA and GMO. Data collection and assembly: MJA, AZ, PB, JCK and GMO. Data analysis and interpretation: MJA, AZ and GMO. All authors contributed to manuscript revision. Final approval of manuscript: All authors.
Funding This study was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario (Grant no. I.PANC.998), the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation (Grant no. not supplied), the Terry Fox Research Institute (Grant no. 1078), and the Pancreatic Cancer Canada Foundation (Grant no. not supplied). The study was also supported by a charitable donation from the Canadian Friends of the Hebrew University (Alex U. Soyka) (Grant no. 800137). SG is the recipient of an Investigator Award from OICR (Award no. IA-051). We acknowledge the contributions of team members at OICR within the Diagnostic Development platform and the Genomics Program (genomics.oicr.on.ca), as well as the contributions of the University Health Network Oncology Biobank.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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