Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

PLoS One. 2022 Aug 19;17(8):e0246778. doi: 10.1371/journal.pone.0246778. eCollection 2022.

Abstract

Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we show across a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The more prevalent actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.

MeSH terms

  • Formaldehyde / therapeutic use
  • High-Throughput Nucleotide Sequencing* / methods
  • Humans
  • Neoplasms* / diagnosis
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Oncogene Proteins, Fusion* / genetics
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors / therapeutic use
  • Semiconductors

Substances

  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Formaldehyde

Grants and funding

The authors received no specific funding for this work. Data analysis conducted in this study was limited to secondary use of information previously collected in the course of normal care. No dedicated funding source was allocated for this study. The funder provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.