title: Parallel screening for ALK, MET and ROS1 alterations in non-small cell lung cancer with implications for daily routine testing.
abstract: OBJECTIVE
  ALK, MET and ROS1 are prognostic and predictive markers in NSCLC, which need to be implemented in daily routine. To evaluate different detection approaches and scoring systems for optimal stratification of patients eligible for mutation testing in the future, we screened a large and unselected cohort of NSCLCs for all three alterations.
  
  
  METHODS
  Using tissue microarrays, 473 surgically resected NSCLCs were tested for ALK and MET expression by IHC and genomic alterations in the ALK, MET and ROS1 gene by FISH. For MET IHC, two different criteria (MetMAb and H-score), for MET FISH, three different scoring systems (UCCC, Cappuzzo, PathVysion) were investigated.
  
  
  RESULTS
  ALK and ROS1 positivity was seen in 2.6% and 1.3% of all ADCs, respectively, but not in pure SCCs. One ROS1 translocated tumor showed additional ROS1 amplification. MET IHC+/FISH+ cases were found in both histological subtypes (8.6% in all NSCLCs; 10.6% in ADCs; 5.0% in SCCs) and were associated with pleural invasion, lymphatic vessel invasion and lymph node metastasis. MET altered ADCs more frequently showed a papillary growth pattern. Whereas ALK testing revealed homogenous results in IHC and FISH, we saw discordant results for MET in about 10% of cases. Both METIHC scoring systems revealed almost identical results. We did not encounter any combined FISH positivity for ALK, MET or ROS1. However, three ALK positive cases harbored MET overexpression.
  
  
  CONCLUSIONS
  In daily routine, IHC could support FISH in the identification of ALK altered NSCLCs. Further research is needed to assess the role of discordant MET results by means of IHC and FISH as well as the relevance of tumors with an increased ROS1 gene copy number.
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jurmeister
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: Berg
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mende
authors.affiliation: Pathology-Berlin, Bioptisches Institut Gemeinschaftspraxis für Pathologie, Lindenberger Weg 27, 13125 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schäper
authors.affiliation: Institute of Pathology, Johannes Wesling Klinikum Minden, Hans-Nolte-Straße 1, 32429 Minden, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Kellner
authors.affiliation: Institute of Pathology, Vivantes Klinikum Berlin, Oranienburger Straße 285, 13437 Berlin, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Herbst
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: maximilian.von-laffert@charite.de.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Laffert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics*; D055088:Early Detection of Cancer; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; FISH; IHC; MET; Non-small cell lung cancer; Predictive biomarkers; ROS1; Targeted therapy