title: Expression profiling-based subtyping identifies novel non-small cell lung cancer subgroups and implicates putative resistance to pemetrexed therapy.
abstract: BACKGROUND
  A challenge of cancer therapy is to optimize therapeutical options to individual patients. Cancers with similar histology may show dramatically different responses to therapy, indicating that a refined approach needs to be developed to classify tumors by intrinsic characteristics that may predict response to chemotherapy. Global expression profile-based classification has the potential to identify such tumor-intrinsic subclasses. Pemetrexed effectiveness has been related to the expression of its target thymidylate synthase. The relatively frequent resistance of squamous cell carcinoma to Pemetrexed is correlated with high levels of thymidylate synthase expression.
  
  
  METHODS
  A global expression profile-based molecular classification of non-small cell lung cancer (NSCLC) was performed. Gene expression was used to predict Pemetrexed responsiveness. The distinct molecular attributes of NSCLCs predicted likely to be resistant to Pemetrexed were bioinformatically characterized. We tested if routine immunohistochemical markers can be used to distinguish putative Pemetrexed responders, predicted by gene signatures, from nonresponders.
  
  
  RESULTS
  Ninety NSCLCs were divided into six subclasses by gene expression signatures. The relevance of this novel phenotyping was linked to other tumor characteristics. Two of the subclasses correlated to putative Pemetrexed resistance. In addition, the identified signature genes characterizing putative Pemetrexed responsiveness predicted therapeutic benefit in a subset of squamous cell carcinoma.
  
  
  CONCLUSIONS
  Gene expression signatures can be used to identify NSCLC subgroups and have potential to predict resistance to Pemetrexed therapy. We suggest that a combination of classical pathological markers can be used to identify molecular tumor subclasses associated with predicted Pemetrexed response.
authors: Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Jun
authors: J
authors: Hou
authors: Margaretha
authors: M
authors: Lambers
authors: Bianca
authors: B
authors: den Hamer
authors: Michael A
authors: MA
authors: den Bakker
authors: Henk C
authors: HC
authors: Hoogsteden
authors: Frank
authors: F
authors: Grosveld
authors: Joost
authors: J
authors: Hegmans
authors: Joachim
authors: J
authors: Aerts
authors: Sjaak
authors: S
authors: Philipsen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D058975:Folate Receptor 1 / Q000378:metabolism; D020869:Gene Expression Profiling; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D053555:Keratin-5 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064151:Minichromosome Maintenance Complex Component 6; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D058978:Reduced Folate Carrier Protein / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D058975:Folate Receptor 1; D005971:Glutamates; D006147:Guanine; D053555:Keratin-5; D008869:Microtubule-Associated Proteins; D064151:Minichromosome Maintenance Complex Component 6; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009687:Nuclear Proteins; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C065500:ASCL1 protein, human; C445325:CDCA7 protein, human; C503940:KRT5 protein, human; C548699:SLC19A1 protein, human; C495901:TP53 protein, human; C504003:TTF1 protein, human; C515549:MAST4 protein, human; C103258:MCM6 protein, human; C421109:multidrug resistance-associated protein 1