TY - JOUR
T1 - RET Fluorescence In Situ Hybridization Analysis Is a Sensitive but Highly Unspecific Screening Method for RET Fusions in Lung Cancer
AU - Radonic, Teodora
AU - Geurts-Giele, W. R. R.
AU - Samsom, Kris G.
AU - Roemen, Guido M. J. M.
AU - von der Thüsen, Jan H.
AU - Thunnissen, Erik
AU - Meijssen, Isabelle C.
AU - Sleddens, Hein F. B. M.
AU - Dinjens, Winand N. M.
AU - Boelens, Mirjam C.
AU - Weijers, Karin
AU - Speel, Ernst Jan M.
AU - Finn, Stephen P.
AU - O'Brien, Cathal
AU - van Wezel, Tom
AU - Cohen, Danielle
AU - Monkhorst, Kim
AU - Roepman, Paul
AU - Dubbink, H. J.
N1 - Funding Information: Disclosure: Dr. von der Thüsen reports receiving personal fees from Eli Lilly during the conduct of the study; personal fees from Bristol-Myers Squibb , Merck Sharp & Dohme , and Roche; and grants from Roche Diagnostics and Bristol-Myers Squibb outside of the submitted work. Dr. Speel reports receiving other fees from Amgen and Bayer and grants from AstraZeneca outside of the submitted work. Dr. Monkhorst reports receiving grants and personal fees from AstraZeneca; personal fees from Merck Sharp & Dohme , Benecke, Bristol-Myers Squibb , AbbVie , Diaceutics, Eli Lilly , Bayer , and Boehringer Ingelheim; personal fees and nonfinancial support from Roche; and nonfinancial support from PGDX, Delfi, and Takeda, outside of the submitted work. Dr. Finn reports receiving personal fees and nonfinancial support from Roche and AstraZeneca; personal fees from Merck Sharp & Dohme; and nonfinancial support from Bayer outside of the submitted work. Dr. Dubbink reports receiving personal fees from Eli Lilly during the conduct of the study; grants, personal fees, and nonfinancial support from AstraZeneca; personal fees from AbbVie, Janssen, Pfizer, PGDx, and Merck Sharp & Dohme outside of the submitted work. The remaining authors declare no conflict of interest. Funding Information: Disclosure: Dr. von der Th?sen reports receiving personal fees from Eli Lilly during the conduct of the study; personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; and grants from Roche Diagnostics and Bristol-Myers Squibb outside of the submitted work. Dr. Speel reports receiving other fees from Amgen and Bayer and grants from AstraZeneca outside of the submitted work. Dr. Monkhorst reports receiving grants and personal fees from AstraZeneca; personal fees from Merck Sharp & Dohme, Benecke, Bristol-Myers Squibb, AbbVie, Diaceutics, Eli Lilly, Bayer, and Boehringer Ingelheim; personal fees and nonfinancial support from Roche; and nonfinancial support from PGDX, Delfi, and Takeda, outside of the submitted work. Dr. Finn reports receiving personal fees and nonfinancial support from Roche and AstraZeneca; personal fees from Merck Sharp & Dohme; and nonfinancial support from Bayer outside of the submitted work. Dr. Dubbink reports receiving personal fees from Eli Lilly during the conduct of the study; grants, personal fees, and nonfinancial support from AstraZeneca; personal fees from AbbVie, Janssen, Pfizer, PGDx, and Merck Sharp & Dohme outside of the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: © 2021 International Association for the Study of Lung Cancer Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - FISH
KW - Non–small cell carcinoma
KW - RET
KW - RNA NGS
UR - http://www.scopus.com/inward/record.url?scp=85103294873&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jtho.2021.01.1619
DO - https://doi.org/10.1016/j.jtho.2021.01.1619
M3 - Article
C2 - 33588111
SN - 1556-0864
VL - 16
SP - 798
EP - 806
JO - Journal of thoracic oncology
JF - Journal of thoracic oncology
IS - 5
ER -