Recurrent and novel fusions detected by targeted RNA sequencing as part of the diagnostic workflow of soft tissue and bone tumours

Author:

Zago Baltazar Rafael1,Claerhout Sofie1ORCID,Vander Borght Sara12,Spans Lien1,Sciot Raphael2,Schöffski Patrick3,Hompes Daphne4,Sinnaeve Friedl5,Wafa Hazem5,Renard Marleen6,van den Hout Mari FCM7,Vernemmen Astrid7,Libbrecht Louis89,De Roo An‐Katrien810,Mazzeo Filomena101112,van Marcke Cédric101112,Deraedt Karen13,Bourgain Claire14,Vanden Bempt Isabelle1ORCID

Affiliation:

1. Department of Human Genetics University Hospitals KU Leuven Leuven Belgium

2. Department of Pathology University Hospitals KU Leuven Leuven Belgium

3. Department of General Medical Oncology University Hospitals KU Leuven Leuven Belgium

4. Department of Surgical Oncology University Hospitals KU Leuven Leuven Belgium

5. Department of Orthopaedic Surgery University Hospitals KU Leuven Leuven Belgium

6. Department of Paediatric Hemato‐Oncology University Hospitals KU Leuven Leuven Belgium

7. Department of Pathology Maastricht University Medical Center+ Maastricht The Netherlands

8. Department of Pathology Cliniques Universitaires Saint‐Luc Brussels Belgium

9. Department of Pathology AZ Groeninge Kortrijk Belgium

10. Institute of Experimental and Clinical Research UCLouvain Brussels Belgium

11. Breast Clinic King Albert II Cancer Institute, Cliniques Universitaires Saint‐Luc Brussels Belgium

12. Department of Medical Oncology King Albert II Cancer Institute, Cliniques Universitaires Saint‐Luc Brussels Belgium

13. Department of Pathology Ziekenhuis Oost‐Limburg Genk Belgium

14. Department of Pathology Imelda Ziekenhuis Bonheiden Belgium

Abstract

AbstractThe identification of gene fusions has become an integral part of soft tissue and bone tumour diagnosis. We investigated the added value of targeted RNA‐based sequencing (targeted RNA‐seq, Archer FusionPlex) to our current molecular diagnostic workflow of these tumours, which is based on fluorescence in situ hybridisation (FISH) for the detection of gene fusions using 25 probes. In a series of 131 diagnostic samples targeted RNA‐seq identified a gene fusion, BCOR internal tandem duplication or ALK deletion in 47 cases (35.9%). For 74 cases, encompassing 137 FISH analyses, concordance between FISH and targeted RNA‐seq was evaluated. A positive or negative FISH result was confirmed by targeted RNA‐seq in 27 out of 49 (55.1%) and 81 out of 88 (92.0%) analyses, respectively. While negative concordance was high, targeted RNA‐seq identified a canonical gene fusion in seven cases despite a negative FISH result. The 22 discordant FISH‐positive analyses showed a lower percentage of rearrangement‐positive nuclei (range 15–41%) compared to the concordant FISH‐positive analyses (>41% of nuclei in 88.9% of cases). Six FISH analyses (in four cases) were finally considered false positive based on histological and targeted RNA‐seq findings. For the EWSR1 FISH probe, we observed a gene‐dependent disparity (p = 0.0020), with 8 out of 35 cases showing a discordance between FISH and targeted RNA‐seq (22.9%). This study demonstrates an added value of targeted RNA‐seq to our current diagnostic workflow of soft tissue and bone tumours in 19 out of 131 cases (14.5%), which we categorised as altered diagnosis (3 cases), added precision (6 cases), or augmented spectrum (10 cases). In the latter subgroup, four novel fusion transcripts were found for which the clinical relevance remains unclear: NAB2::NCOA2, YAP1::NUTM2B, HSPA8::BRAF, and PDE2A::PLAG1. Overall, targeted RNA‐seq has proven extremely valuable in the diagnostic workflow of soft tissue and bone tumours.

Funder

Universitaire Ziekenhuizen Leuven, KU Leuven

Publisher

Wiley

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