INTRODUCTION: Chromosomal rearrangements involving the gene ROS1 define a distinct molecular subset of NSCLCs with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in EGFR and KRAS. METHODS: We identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma receptor tyrosine kinase gene (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through the commercial FoundationOne assay (Foundation Medicine, Cambridge, MA). RESULTS: Among 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent noncanonical KRAS I24N mutation of unknown biological significance. In a separate ROS1 fluorescence in situ hybridization-positive case, targeted sequencing failed to confirm a ROS1 fusion but instead identified a KRAS G13D mutation. No concurrent mutations in B-Raf proto-oncogene, serine/threonine kinase gene (BRAF), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), AKT/serine threonine kinase 1 gene (AKT1), or mitogen-activated protein kinase kinase 1 gene (MAP2K1) were detected. Analysis of an independent data set of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (one of 166) and KRAS (three of 166) and no cases with co-occurring ROS1 and ALK rearrangements. CONCLUSIONS: ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.
INTRODUCTION: Chromosomal rearrangements involving the gene ROS1 define a distinct molecular subset of NSCLCs with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in EGFR and KRAS. METHODS: We identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma receptor tyrosine kinase gene (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through the commercial FoundationOne assay (Foundation Medicine, Cambridge, MA). RESULTS: Among 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent noncanonical KRASI24N mutation of unknown biological significance. In a separate ROS1 fluorescence in situ hybridization-positive case, targeted sequencing failed to confirm a ROS1 fusion but instead identified a KRASG13D mutation. No concurrent mutations in B-Raf proto-oncogene, serine/threonine kinase gene (BRAF), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), AKT/serine threonine kinase 1 gene (AKT1), or mitogen-activated protein kinase kinase 1 gene (MAP2K1) were detected. Analysis of an independent data set of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (one of 166) and KRAS (three of 166) and no cases with co-occurring ROS1 and ALK rearrangements. CONCLUSIONS:ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.
Authors: Arne Warth; Thomas Muley; Hendrik Dienemann; Benjamin Goeppert; Albrecht Stenzinger; Philipp A Schnabel; Peter Schirmacher; Roland Penzel; Wilko Weichert Journal: Histopathology Date: 2014-04-03 Impact factor: 5.087
Authors: Kristin Bergethon; Alice T Shaw; Sai-Hong Ignatius Ou; Ryohei Katayama; Christine M Lovly; Nerina T McDonald; Pierre P Massion; Christina Siwak-Tapp; Adriana Gonzalez; Rong Fang; Eugene J Mark; Julie M Batten; Haiquan Chen; Keith D Wilner; Eunice L Kwak; Jeffrey W Clark; David P Carbone; Hongbin Ji; Jeffrey A Engelman; Mari Mino-Kenudson; William Pao; A John Iafrate Journal: J Clin Oncol Date: 2012-01-03 Impact factor: 44.544
Authors: Marcel Wiesweg; Wilfried E E Eberhardt; Henning Reis; Saskia Ting; Nikoleta Savvidou; Charlotte Skiba; Thomas Herold; Daniel C Christoph; Johannes Meiler; Karl Worm; Stefan Kasper; Dirk Theegarten; Jörg Hense; Thomas Hager; Kaid Darwiche; Filiz Oezkan; Clemens Aigner; Stefan Welter; Hilmar Kühl; Martin Stuschke; Kurt W Schmid; Martin Schuler Journal: J Thorac Oncol Date: 2016-08-27 Impact factor: 15.609
Authors: Mark M Awad; Ryohei Katayama; Michele McTigue; Wei Liu; Ya-Li Deng; Alexei Brooun; Luc Friboulet; Donghui Huang; Matthew D Falk; Sergei Timofeevski; Keith D Wilner; Elizabeth L Lockerman; Tahsin M Khan; Sidra Mahmood; Justin F Gainor; Subba R Digumarthy; James R Stone; Mari Mino-Kenudson; James G Christensen; A John Iafrate; Jeffrey A Engelman; Alice T Shaw Journal: N Engl J Med Date: 2013-06-01 Impact factor: 91.245
Authors: Klarisa Rikova; Ailan Guo; Qingfu Zeng; Anthony Possemato; Jian Yu; Herbert Haack; Julie Nardone; Kimberly Lee; Cynthia Reeves; Yu Li; Yerong Hu; Zhiping Tan; Matthew Stokes; Laura Sullivan; Jeffrey Mitchell; Randy Wetzel; Joan Macneill; Jian Min Ren; Jin Yuan; Corey E Bakalarski; Judit Villen; Jon M Kornhauser; Bradley Smith; Daiqiang Li; Xinmin Zhou; Steven P Gygi; Ting-Lei Gu; Roberto D Polakiewicz; John Rush; Michael J Comb Journal: Cell Date: 2007-12-14 Impact factor: 41.582
Authors: H R Kim; S M Lim; H J Kim; S K Hwang; J K Park; E Shin; M K Bae; S-H I Ou; J Wang; S S Jewell; D R Kang; R A Soo; H Haack; J H Kim; H S Shim; B C Cho Journal: Ann Oncol Date: 2013-06-19 Impact factor: 32.976
Authors: Simon A Forbes; David Beare; Prasad Gunasekaran; Kenric Leung; Nidhi Bindal; Harry Boutselakis; Minjie Ding; Sally Bamford; Charlotte Cole; Sari Ward; Chai Yin Kok; Mingming Jia; Tisham De; Jon W Teague; Michael R Stratton; Ultan McDermott; Peter J Campbell Journal: Nucleic Acids Res Date: 2014-10-29 Impact factor: 16.971
Authors: D G Bebb; J Agulnik; R Albadine; S Banerji; G Bigras; C Butts; C Couture; J C Cutz; P Desmeules; D N Ionescu; N B Leighl; B Melosky; W Morzycki; F Rashid-Kolvear; Clin Lab; H S Sekhon; A C Smith; T L Stockley; E Torlakovic; Z Xu; M S Tsao Journal: Curr Oncol Date: 2019-08-01 Impact factor: 3.677
Authors: Kurtis D Davies; Anh T Le; Jamie Sheren; Hala Nijmeh; Katherine Gowan; Kenneth L Jones; Marileila Varella-Garcia; Dara L Aisner; Robert C Doebele Journal: J Thorac Oncol Date: 2018-06-20 Impact factor: 15.609