TY - JOUR
T1 - Cervical chromosome 9 polysomy
T2 - Validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial
AU - Kim, Heung Gon
AU - Yamal, Jose Miguel
AU - Xu, Xiao Chun
AU - Hu, Wei
AU - Boiko, Iouri
AU - Linares, Adriana
AU - Vlastos, Anne Therese
AU - Atkinson, E. Neely
AU - Malpica, Anais
AU - Hittelman, Walter N.
AU - Follen, Michele
N1 - Funding Information:
Supported by National Cancer Institute Grant CN-25483-02.
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
KW - Cervix
KW - Chemoprevention
KW - Chromosome 9 polysomy
KW - Randomized clinical trials
KW - Surrogate end point biomarkers
UR - http://www.scopus.com/inward/record.url?scp=28844466442&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28844466442&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2005.07.039
DO - 10.1016/j.ygyno.2005.07.039
M3 - Article
C2 - 16154183
AN - SCOPUS:28844466442
SN - 0090-8258
VL - 99
SP - S32-S37
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3 SUPPL.
ER -