title: TOP1 gene copy numbers in colorectal cancer samples and cell lines and their association to in vitro drug sensitivity.
abstract: OBJECTIVE
  A positive relationship between topoisomerase-1 (TOP1) protein and sensitivity toward the TOP1 inhibitor irinotecan has been reported in patients with metastatic colorectal cancer (mCRC). In this study, we analyzed TOP1 gene copy number variation in tumor tissue from CRC patients and CRC cell lines with different sensitivities to the TOP1 inhibitor SN-38 and oxaliplatin.
  
  
  METHODS
  A TOP1 gene probe with a chromosome 20 centromere (CEN-20) reference probe was applied on normal mucosa and on tumor tissue from 50 stage III CRC patients. Additionally, associations between TOP1/CEN-20 ratio and in vitro sensitivity to SN-38 (irinotecan) and oxaliplatin were tested on 10 CRC cell lines. Results. In the malignant epithelium, 84% of the samples demonstrated an increased TOP1 gene copy number and 64% had an increased TOP1/CEN-20 ratio compared with the non-affected mucosa. Sixteen (32%) of the tumors had a ratio of ≥ 1.5 and 9 (18%) of these had a ratio of ≥ 2.0. A positive association was observed between the TOP1 gene copy number and the TOP1/CEN-20 ratio and in vitro sensitivity toward SN-38, but not toward oxaliplatin.
  
  
  CONCLUSIONS
  A large fraction of the clinical samples demonstrated increased TOP1 gene copy number and increased TOP1/CEN-20 ratio. The cell line study suggested an association between TOP1 gene copy number or TOP1/CEN-20 ratio and sensitivity to irinotecan but not oxaliplatin.
authors.affiliation: Department of Veterinary Disease Biology, Section of Pathobiology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg C, Denmark. romer@life.ku.dk
authors.forename: Maria Unni
authors.initials: MU
authors.lastname: Rømer
authors.forename: Niels Frank
authors.initials: NF
authors.lastname: Jensen
authors.forename: Signe Lykke
authors.initials: SL
authors.lastname: Nielsen
authors.forename: Sven
authors.initials: S
authors.lastname: Müller
authors.forename: Kirsten Vang
authors.initials: KV
authors.lastname: Nielsen
authors.forename: Hans Jørgen
authors.initials: HJ
authors.lastname: Nielsen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics*; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D018709:Statistics, Nonparametric
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin