title: ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer.
abstract: BACKGROUND
  Increased incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) with ALK translocations was postulated, however, ALK gene aberrations in NSCLC-BM have not been investigated so far.
  
  
  METHODS
  We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors.
  
  
  RESULTS
  ALK translocations were found in 4/151 (2.6%; 3 of them involving EML4) of BM of adenocarcinomas (AC), 1/9 (11.1%) of adenosquamous carcinomas (ASC), 0/5 of squamous cell carcinomas (SCC) and 0/10 of large cell carcinomas (LCC). Rearrangement of ALK without involvement of EML4 was seen in 1 AC-BM and rearrangement of EML4 without involvement of ALK in 3 AC-BM, 1 ASC-BM and 1 LCC. ALK amplifications without gene rearrangements were found in BM of 16/151 (10.6%) AC, 2/5 (40%) SCC, 0/9 ASC and one LCC. ALK translocation status was constant between BM and primary tumors in 16 evaluable cases including two cases with ALK-EML4 translocations Among these 16 cases ALK amplification was seen in two BM and none of the primary tumors. All cases with translocations but not with amplifications of ALK showed protein expression. We found no association of ALK gene status with patient age, gender or overall survival time.
  
  
  CONCLUSIONS
  ALK translocations and amplifications are found in approximately 3% and 11% of NSCLC-BM, respectively. While ALK translocations appear to be constant between primary tumors and BM, amplifications seem to be more prevalent in BM. ALK translocation, but not ALK amplification is associated with ALK protein overexpression. Further studies are needed to determine whether NSCLC-BM patients with ALK gene aberrations may benefit from specific inhibitor therapy.
authors: Department of Medicine I, Medical University of Vienna, Austria. matthias.preusser@meduniwien.ac.at
authors: Matthias
authors: M
authors: Preusser
authors: Anna S
authors: AS
authors: Berghoff
authors: Ayseguel
authors: A
authors: Ilhan-Mutlu
authors: Manuel
authors: M
authors: Magerle
authors: Carina
authors: C
authors: Dinhof
authors: Georg
authors: G
authors: Widhalm
authors: Karin
authors: K
authors: Dieckmann
authors: Christine
authors: C
authors: Marosi
authors: Adelheid
authors: A
authors: Wöhrer
authors: Monika
authors: M
authors: Hackl
authors: Sabine
authors: S
authors: Zöchbauer-Müller
authors: Andreas
authors: A
authors: von Deimling
authors: Sebastian F
authors: SF
authors: Schoppmann
authors: Christoph C
authors: CC
authors: Zielinski
authors: Berthold
authors: B
authors: Streubel
authors: Peter
authors: P
authors: Birner
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D007446:Chromosome Inversion / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics; D046888:Tissue Array Analysis; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases