Teodora Radonic1, W R R Geurts-Giele2, Kris G Samsom3, Guido M J M Roemen4, Jan H von der Thüsen2, Erik Thunnissen5, Isabelle C Meijssen2, Hein F B M Sleddens2, Winand N M Dinjens2, Mirjam C Boelens3, Karin Weijers5, Ernst Jan M Speel6, Stephen P Finn7, Cathal O'Brien7, Tom van Wezel8, Danielle Cohen9, Kim Monkhorst3, Paul Roepman10, H J Dubbink2. 1. Department of Pathology, Cancer Center Amsterdam, Vrije University, Amsterdam University Medical Center, Amsterdam, The Netherlands. Electronic address: T.radonic@amsterdamumc.nl. 2. Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 3. Department of Pathology, Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands. 5. Department of Pathology, Cancer Center Amsterdam, Vrije University, Amsterdam University Medical Center, Amsterdam, The Netherlands. 6. Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands; School for Oncology and Developmental Biology (GROW), Maastricht, The Netherlands. 7. Department of Histopathology, St. James's Hospital and Trinity College Dublin, Dublin, Ireland; Cancer Molecular Diagnostics, St. James's Hospital and Trinity College Dublin, Dublin, Ireland; Thoracic Oncology Research Group, Trinity Translational Medical Institute, St. James's Hospital and Trinity College Dublin, Dublin, Ireland. 8. Department of Pathology, Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 9. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 10. Hartwig Medical Foundation, Amsterdam, The Netherlands.
Abstract
INTRODUCTION: RET gene fusions are established oncogenic drivers in 1% of NSCLC. Accurate detection of advanced patients with RET fusions is essential to ensure optimal therapy choice. We investigated the performance of fluorescence in situ hybridization (FISH) as a diagnostic test for detecting functional RET fusions. METHODS: Between January 2016 and November 2019, a total of 4873 patients with NSCLC were routinely screened for RET fusions using either FISH (n = 2858) or targeted RNA next-generation sequencing (NGS) (n = 2015). If sufficient material was available, positive cases were analyzed by both methods (n = 39) and multiple FISH assays (n = 17). In an independent cohort of 520 patients with NSCLC, whole-genome sequencing data were investigated for disruptive structural variations and functional fusions in the RET and compared with ALK and ROS1 loci. RESULTS: FISH analysis revealed RET rearrangement in 48 of 2858 cases; of 30 rearranged cases double tested with NGS, only nine had a functional RET fusion. RNA NGS yielded RET fusions in 14 of 2015 cases; all nine cases double tested by FISH had RET locus rearrangement. Of these 18 verified RET fusion cases, 16 had a split signal and two a complex rearrangement by FISH. By whole-genome sequencing, the prevalence of functional fusions compared with all disruptive events was lower in the RET (4 of 9, 44%) than the ALK (27 of 34, 79%) and ROS1 (9 of 12, 75%) loci. CONCLUSIONS: FISH is a sensitive but unspecific technique for RET screening, always requiring a confirmation using an orthogonal technique, owing to frequently occurring RET rearrangements not resulting in functional fusions in NSCLC.
INTRODUCTION:RET gene fusions are established oncogenic drivers in 1% of NSCLC. Accurate detection of advanced patients with RET fusions is essential to ensure optimal therapy choice. We investigated the performance of fluorescence in situ hybridization (FISH) as a diagnostic test for detecting functional RET fusions. METHODS: Between January 2016 and November 2019, a total of 4873 patients with NSCLC were routinely screened for RET fusions using either FISH (n = 2858) or targeted RNA next-generation sequencing (NGS) (n = 2015). If sufficient material was available, positive cases were analyzed by both methods (n = 39) and multiple FISH assays (n = 17). In an independent cohort of 520 patients with NSCLC, whole-genome sequencing data were investigated for disruptive structural variations and functional fusions in the RET and compared with ALK and ROS1 loci. RESULTS: FISH analysis revealed RET rearrangement in 48 of 2858 cases; of 30 rearranged cases double tested with NGS, only nine had a functional RET fusion. RNA NGS yielded RET fusions in 14 of 2015 cases; all nine cases double tested by FISH had RET locus rearrangement. Of these 18 verified RET fusion cases, 16 had a split signal and two a complex rearrangement by FISH. By whole-genome sequencing, the prevalence of functional fusions compared with all disruptive events was lower in the RET (4 of 9, 44%) than the ALK (27 of 34, 79%) and ROS1 (9 of 12, 75%) loci. CONCLUSIONS: FISH is a sensitive but unspecific technique for RET screening, always requiring a confirmation using an orthogonal technique, owing to frequently occurring RET rearrangements not resulting in functional fusions in NSCLC.
Authors: Verona E Bergshoeff; Maschenka C A Balkenhol; Annick Haesevoets; Andrea Ruland; Michelene N Chenault; Rik C Nelissen; Carine J Peutz; Ruud Clarijs; Jeroen A W M Van der Laak; Robert P Takes; Michiel W Van den Brekel; Marie-Louise F Van Velthuysen; Frans C S Ramaekers; Bernd Kremer; Ernst-Jan M Speel Journal: Cancers (Basel) Date: 2022-07-03 Impact factor: 6.575
Authors: J Thouvenin; C Van Marcke; L Decoster; G Raicevic; K Punie; M Vandenbulcke; R Salgado; E Van Valckenborgh; B Maes; S Joris; D Vander Steichel; K Vranken; S Jacobs; F Dedeurwaerdere; G Martens; H Devos; F P Duhoux; M Rasschaert; P Pauwels; K Geboes; J Collignon; S Tejpar; J-L Canon; M Peeters; A Rutten; T Van de Mooter; J Vermeij; D Schrijvers; W Demey; W Lybaert; J Van Huysse; J Mebis; A Awada; K B M Claes; A Hebrant; J Van der Meulen; B Delafontaine; I Vanden Bempt; J Maetens; M de Hemptinne; S Rottey; P Aftimos; J De Grève Journal: ESMO Open Date: 2022-08-12
Authors: Henri B Wolff; Elisabeth M P Steeghs; Zakile A Mfumbilwa; Harry J M Groen; Eddy M Adang; Stefan M Willems; Katrien Grünberg; Ed Schuuring; Marjolijn J L Ligtenberg; Bastiaan B J Tops; Veerle M H Coupé Journal: JCO Precis Oncol Date: 2022-07
Authors: Mehtap Derya Aydemirli; Marieke Snel; Tom van Wezel; Dina Ruano; Christianne M H Obbink; Wilbert B van den Hout; Abbey Schepers; Hans Morreau Journal: Endocrinol Diabetes Metab Date: 2021-09-02