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Allen, Michael J; Zhang, Amy; Bavi, Prashant; Kim, Jaeseung C; Jang, Gun Ho; Kelly, Deirdre; Perera, Sheron; Denroche, Rob E; Notta, Faiyaz; Wilson, Julie M; Dodd, Anna; Ramotar, Stephanie; Hutchinson, Shawn; Fischer, Sandra E; Grant, Robert C; Gallinger, Steven; Knox, Jennifer J; O'Kane, Grainne M

Molecular characterisation of pancreatic ductal adenocarcinoma withNTRKfusions and review of the literature

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  • Medientyp: E-Artikel
  • Titel: Molecular characterisation of pancreatic ductal adenocarcinoma withNTRKfusions and review of the literature
  • Beteiligte: Allen, Michael J; Zhang, Amy; Bavi, Prashant; Kim, Jaeseung C; Jang, Gun Ho; Kelly, Deirdre; Perera, Sheron; Denroche, Rob E; Notta, Faiyaz; Wilson, Julie M; Dodd, Anna; Ramotar, Stephanie; Hutchinson, Shawn; Fischer, Sandra E; Grant, Robert C; Gallinger, Steven; Knox, Jennifer J; O'Kane, Grainne M
  • Erschienen: BMJ, 2023
  • Erschienen in: Journal of Clinical Pathology
  • Sprache: Englisch
  • DOI: 10.1136/jclinpath-2021-207781
  • ISSN: 0021-9746; 1472-4146
  • Schlagwörter: General Medicine ; Pathology and Forensic Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Aims</jats:title><jats:p>The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in<jats:italic>KRAS</jats:italic>with variants in<jats:italic>TP53</jats:italic>,<jats:italic>CDKN2A</jats:italic>and<jats:italic>SMAD4</jats:italic>also prevalent. The presence of oncogenic fusions including<jats:italic>NTRK</jats:italic>fusions are rare but important to identify. Here we ascertain the prevalence of<jats:italic>NTRK</jats:italic>fusions and document their genomic characteristics in a large series of PDAC.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an<jats:italic>NTRK</jats:italic>fusion, two<jats:italic>EML4-NTRK3</jats:italic>(<jats:italic>KRAS</jats:italic>-WT) and a single novel<jats:italic>KANK1-NTRK3</jats:italic>fusion. The latter occurring in the presence of a subclonal<jats:italic>KRAS</jats:italic>mutation. Typical PDAC drivers were present including mutations in<jats:italic>TP53</jats:italic>and<jats:italic>CDKN2A</jats:italic>. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of<jats:italic>NTRK</jats:italic>fusions was 0.8% (3/400), while in<jats:italic>KRAS</jats:italic>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<jats:italic>KANK1-NTRK3</jats:italic>fusion but positive in a<jats:italic>EML4-NTRK3</jats:italic>case, highlighting lower sensitivity of IHC.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p><jats:italic>NTRK</jats:italic>fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for<jats:italic>KRAS</jats:italic>mutations and subsequent RNA-based screening could help identify these cases in PDAC.</jats:p></jats:sec>