title: Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma.
abstract: OBJECTIVE
  Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options.
  
  
  METHODS
  We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with >75% tumor cell content.
  
  
  RESULTS
  EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3-TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3-TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3-TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib.
  
  
  CONCLUSIONS
  FGFR3-TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Dodge
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Seung-Il
authors.initials: SI
authors.lastname: Park
authors.affiliation: Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Jhingook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Lauren
authors.initials: L
authors.lastname: Young
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Phil J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Department of Pathology and Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Kiara J
authors.initials: KJ
authors.lastname: Munir
authors.affiliation: Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005787:Gene Frequency; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012307:Risk Factors; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D011743:Pyrimidines; C120551:TACC3 protein, human; C568950:infigratinib; D066246:ErbB Receptors; D051498:Receptor, Fibroblast Growth Factor, Type 3