title: ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non-Small Cell Lung Cancer.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Ferris
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: ashaw1@mgh.harvard.edu.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D005260:Female; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050596:Oncogene Fusion; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Concurrent mutations; NSCLC; Non–small cell lung cancer; ROS1