Combined clinical and genetic testing algorithm for cervical cancer diagnosis.
BACKGROUND
Opportunistic screening in hospitals is widely used to effectively reduce the incidence rate of cervical cancer in China and other developing countries. This study aimed to identify clinical risk factor algorithms that combine gynecologic examination and molecular testing (paired box gene 1 (PAX1) or zinc finger protein 582 (ZNF582) methylation or HPV16/18) results to improve diagnostic accuracy.


METHODS
The delta Cp of methylated PAX1 and ZNF582 was obtained via quantitative methylation-specific PCR in a training set (57 CIN2- and 43 cervical intraepithelial neoplasia ≥grade 3 (CIN3+) women), and the individual and combination gene sensitivities and specificities were determined. The detection accuracy of three algorithms combining gynecologic findings and genetic test results was then compared in a randomized case-control study comprising 449 women referred for colposcopic examination by gynecologists in the outpatient department of Xiangya Hospital between November 2011 and March 2013.


RESULTS
Significant association was observed between CIN3+ and methylated PAX1 or ZNF582 in combination with HPV16/18 (OR:15.52, 95 % CI:7.73-31.18). The sensitivities and specificities of methylated PAX1 or ZNF582 combined with HPV16/18 for CIN3+ women were 89.2 and 76.0 %, or 85.4 and 80.1 %, respectively. Of the three algorithms applied to cohort data and validated in the study, two indicated 100 % sensitivity in detecting cervical cancer and a low rate of referrals for colposcopy.


CONCLUSIONS
These algorithms might contribute to precise and objective cervical cancer diagnostics in the outpatient departments of hospitals in countries with high mortality and low screening rates or areas with uneven resource distribution.
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, 410078 People's Republic of China.|Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410008 People's Republic of China.|iStat Biomedical Co. Ltd., New Taipei City, 22102 Taiwan.
Yu-Ligh
YL
Liou
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, 410078 People's Republic of China.
Tao-Lan
TL
Zhang
Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Hunan, 410008 People's Republic of China.
Tian
T
Yan
iStat Biomedical Co. Ltd., New Taipei City, 22102 Taiwan.
Ching-Tung
CT
Yeh
Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Hunan, 410008 People's Republic of China.
Ya-Nan
YN
Kang
Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Hunan, 410008 People's Republic of China.
Lanqin
L
Cao
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, 410078 People's Republic of China.
Nayiyuan
N
Wu
iStat Biomedical Co. Ltd., New Taipei City, 22102 Taiwan.
Chi-Feng
CF
Chang
iStat Biomedical Co. Ltd., New Taipei City, 22102 Taiwan.
Huei-Jen
HJ
Wang
iStat Biomedical Co. Ltd., New Taipei City, 22102 Taiwan.|Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3200 USA.
Carolyn
C
Yen
Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hualien, 97002 Taiwan.|Institute of Medical Science, Tzu Chi University, Hualien, 97002 Taiwan.|Center for Cervical Cancer Prevention, Department of Research Buddhist, Tzu Chi General Hospital, Hualien, 97002 Taiwan.
Tang-Yuan
TY
Chu
Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Hunan, 410008 People's Republic of China.
Yi
Y
Zhang
Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Hunan, 410008 People's Republic of China.
Yu
Y
Zhang
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan, 410078 People's Republic of China.|Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410008 People's Republic of China.
Honghao
H
Zhou
D000328:Adult; D000368:Aged; D000465:Algorithms; D016022:Case-Control Studies; D003127:Colposcopy; D019175:DNA Methylation; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D052162:Human papillomavirus 16 / Q000302:isolation & purification; D052161:Human papillomavirus 18 / Q000302:isolation & purification; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D051761:Paired Box Transcription Factors / Q000235:genetics; D011897:Random Allocation; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000821:virology; D014626:Vaginal Smears
D051741:Kruppel-Like Transcription Factors; D051761:Paired Box Transcription Factors; C577358:ZNF582 protein, human; C070835:PAX1 transcription factor
Algorithm; Biomarkers; Cervical cancer; DNA methylation; HPV16/18; PAX1; ZNF582