Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.
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.
Kim
Heung Gon
HG
Department of Cellular and Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Yamal
Jose-Miguel
JM
Xu
Xiao-Chun
XC
Hu
Wei
W
Boiko
Iouri
I
Linares
Adriana
A
Vlastos
Anne-Therese
AT
Atkinson
E Neely
EN
Malpica
Anais
A
Hittelman
Walter N
WN
Follen
Michele
M
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*
D016588:Anticarcinogenic Agents; D010919:Placebos; D017313:Fenretinide