title: An explorative analysis of ERCC1-19q13 copy number aberrations in a chemonaive stage III colorectal cancer cohort.
abstract: BACKGROUND
  Platinum-based chemotherapy has long been used in the treatment of a variety of cancers and functions by inducing DNA damage. ERCC1 and ERCC4 are involved in the removal of this damage and have previously been implicated in resistance to platinum compounds. The aim of the current investigation is to determine the presence, frequency and prognostic impact of ERCC1 or ERCC4 gene copy number alterations in colorectal cancer (CRC).
  
  
  METHODS
  Fluorescent in situ hybridization probes directed at ERCC1 and ERCC4 with relevant reference probes were constructed. Probes were tested in a CRC cell line panel and in tumor sections from 152 stage III CRC chemonaive patients. Relationships between biomarker status and clinical endpoints (overall survival, time to recurrence, and local recurrence in rectal cancer) were analyzed by survival statistics.
  
  
  RESULTS
  ERCC1-19q13 copy number alterations were observed in a single cell line metaphase (HT29). In patient material, ERCC1-19q13 copy number gains (ERCC1-19q13/CEN-2 ≥ 1.5) were detected in 27.0% of specimens, whereas ERCC1-19q13 deletions (ERCC1-19q13/CEN-2 < 0.8) were only detected in 1.3%. ERCC1-19q13 gain was significantly associated with longer survival (multivariate analysis, HR: 0.45, 95% CI: 0.20-1.00, p = 0.049) in patients with colon tumors, but not rectal tumors. No ERCC4 aberrations were detected and scoring was discontinued after 50 patients.
  
  
  CONCLUSIONS
  ERCC1-19q13 copy number gains occur frequently in stage III CRC and influences survival in patients with colon tumors. Future studies will investigate the effect of ERCC1-19q13 aberrations in a platinum-treated patient population with the aim of developing a predictive biomarker profile for oxaliplatin sensitivity in CRC.
authors.affiliation: R&D, Dako A/S, Produktionsvej 42, Glostrup DK-2600, Denmark. dhsmith@dako.com.
authors.forename: David Hersi
authors.initials: DH
authors.lastname: Smith
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Niels Frank
authors.initials: NF
authors.lastname: Jensen
authors.forename: Bo
authors.initials: B
authors.lastname: Markussen
authors.forename: Sven
authors.initials: S
authors.lastname: Müller
authors.forename: Hans Jørgen
authors.initials: HJ
authors.lastname: Nielsen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Kirsten Vang
authors.initials: KV
authors.lastname: Nielsen
mesh_terms: D000367:Age Factors; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002888:Chromosomes, Human, Pair 19; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D012737:Sex Factors
chemical_list: D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases