title: Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.
abstract: BACKGROUND
  Several genetic alterations have been described in cervical cancers including: human papillomavirus (HPV) E6 and E7 oncoproteins, subtle sequence changes, alterations in chromosome number, chromosome translocations, and gene amplifications. This report focuses on establishing chromosome 9 polysomy as a cervical biomarker of chromosome instability and using it in a chemoprevention trial. Chromosomal instability is a feature of most human cancers and is probably an early event in the process.
  
  
  METHODS
  We used 37 cervical cone specimens to validate chromosome 9 polysomy as a biomarker and then tested its modulation in a randomized clinical trial of 4-hydroxyphenylretinamide (4-HPR) in 39 patients with three blinded histopathologic reviews. No confounders were identified. In the present study, immunohistocytochemical analysis of Chromosome 9 polysomy was carried out and quantitatively measured.
  
  
  RESULTS
  The Cell Index, the ratio of the number of total chromosome 9 copies to the total number of ells, increases significantly in archival samples as the cervix changes from normal to CIN to invasive cancer. In the chemoprevention trial, chromosome 9 polysomy was used as a biomarker and supported the histological analysis showing that 4-HPR impaired the natural regression response.
  
  
  CONCLUSIONS
  Chromosome 9 polysomy appears to be a marker of genetic instability that can be used in chemoprevention trials as a surrogate endpoint biomarker. In this randomized trial of 4-HPR, the chromosome 9 polysomy measurements supported the clinical histopathologic reading in a quantitative manner suggesting that 4-HPR at 200 mg/day may have been inhibiting the regression seen in the placebo arm by inducing genetic instability.
authors.affiliation: Department of Cellular and Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Heung Gon
authors.initials: HG
authors.lastname: Kim
authors.forename: Jose-Miguel
authors.initials: JM
authors.lastname: Yamal
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Iouri
authors.initials: I
authors.lastname: Boiko
authors.forename: Adriana
authors.initials: A
authors.lastname: Linares
authors.forename: Anne-Therese
authors.initials: AT
authors.lastname: Vlastos
authors.forename: E Neely
authors.initials: EN
authors.lastname: Atkinson
authors.forename: Anais
authors.initials: A
authors.lastname: Malpica
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Michele
authors.initials: M
authors.lastname: Follen
mesh_terms: D000782:Aneuploidy; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D016588:Anticarcinogenic Agents; D010919:Placebos; D017313:Fenretinide