Molecular characterisation of pancreatic ductal adenocarcinoma with fusions and review of the literature.

AIMS

The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in with variants in , and also prevalent. The presence of oncogenic fusions including fusions are rare but important to identify. Here we ascertain the prevalence of 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 fusion, two (-WT) and a single novel fusion. The latter occurring in the presence of a subclonal mutation. Typical PDAC drivers were present including mutations in and . Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of fusions was 0.8% (3/400), while in 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 fusion but positive in a case, highlighting lower sensitivity of IHC.

CONCLUSION

fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for mutations and subsequent RNA-based screening could help identify these cases in PDAC.