title: Thymidylate synthase protein expression by IHC and gene copy number by SISH correlate and show great variability in non-small cell lung cancer.
abstract: BACKGROUND
  Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to TS-targeting drugs, e.g., pemetrexed.
  
  
  METHODS
  TS protein expression (PE) and gene copy number (GCN) were assayed using immunohistochemistry and silver in situ hybridization, respectively, on primary tumors of 189 resected non-small cell lung patients. Associations with pathological and clinical features and prognosis were explored.
  
  
  RESULTS
  Median immunohistochemistry H-score was 220 (range, 10-380) on a 0 to 400 scale; 17% of the patients had a TS expression of 300 or more. TS PE expression did not significantly differ by histology and did not significantly associate with disease-free survival (DFS) or overall survival (OS). However, there was a tendency for increased DFS (p = 0.12) and OS (p = 0.12) in PE positive (>median) squamous-cell carcinoma (SCC) patients. Median GCN was 2.5 genes/nucleus (range, 1.4-9.6); 29% of patients had GCN of 3 or more, 7% of 4 or more and 0.8% amplification. GCN differed by histology (p = 0.015); 50% of SCCs having GCN more than 2.5 versus 32% of adenocarcinomas. There was no significant relationship between TS GCN and DFS or OS; however, a trend toward better DFS (p = 0.18) and OS (p = 0.10) with increased GCN in SCCs was observed. TS GCN was significantly correlated with PE (r = 0.30, p = 0.0009).
  
  
  CONCLUSIONS
  TS PE and GCN vary widely in non-small cell lung and correlate significantly with each other. TS GCN is higher in SCCs, whereas TS PE does not associate with histological subtypes, clinical features, or survival. Variability of TS PE and GCN may indicate potential benefit from pemetrexed therapy in selected SCC patients.
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Murry W
authors.initials: MW
authors.lastname: Wynes
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Konopa
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.forename: Bernadette
authors.initials: B
authors.lastname: Reyna-Asuncion
authors.forename: James
authors.initials: J
authors.lastname: Ranger-Moore
authors.forename: Adam
authors.initials: A
authors.lastname: Sternau
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Christoph
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D040081:Protein Array Analysis; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D013940:Thymidylate Synthase