title: Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer.
abstract: BACKGROUND
  Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non-small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples.
  
  
  METHODS
  FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number.
  
  
  RESULTS
  FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression.
  
  
  CONCLUSIONS
  A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy.
authors.affiliation: *Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Institute, Shanghai, People's Republic of China; †Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ‡Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; §Institute of Pathology, University Hospital Cologne, Medical Centre, Cologne, Germany; ‖Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ¶Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and #Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Institute, Shanghai, People's Republic of China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Andrzej
authors.initials: A
authors.lastname: Badzio
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Boyle
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Kowalewski
authors.forename: Kim
authors.initials: K
authors.lastname: Ellison
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008024:Ligands; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008024:Ligands; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1