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Published on: June 16, 2017
Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions
Mary Jo Fackler1, Madison Pleas1, Youran Li1
1Women's Malignancies Program, Department of Oncology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Rm 144, CRB1, Baltimore, MD, 21231, USA.
A novel 5-gene methylated DNA marker panel accurately detects high-risk cervical lesions, including squamous cell carcinoma (SCC) and high-grade squamous intraepithelial lesions (HSIL), in cervical smears. This molecular test offers improved accuracy for cervical cancer screening and timely treatment.
Area of Science:
- Oncology
- Molecular Diagnostics
- Gynecologic Pathology
Background:
- Cervical cancer is a significant global health issue, particularly in developing nations.
- Current human papilloma virus (HPV) testing identifies risk but doesn't precisely diagnose neoplasia.
- There is a need for accurate molecular tests to detect high-risk cervical lesions.
Purpose of the Study:
- To investigate the accuracy of a quantitative molecular test measuring methylated DNA markers for identifying high-risk cervical lesions.
- To develop and validate a panel of methylated DNA markers for cervical cancer detection.
Main Methods:
- Marker discovery utilized the TCGA-CESC Infinium Methylation 450K Array database and three public datasets.
- A 5-gene panel (FMN2, EDNRB, ZNF671, TBXT, MOS) was technically validated using Quantitative Multiplex-Methylation-Specific PCR.
- Validation was performed on tissue sections (N=252) and cervical smears (N=244) from the USA, South Africa, and Vietnam.
Main Results:
- The 5-gene panel demonstrated high sensitivity and specificity in detecting squamous cell carcinoma (SCC) and high-grade squamous intraepithelial lesions (HSIL) in cervical tissues and smears.
- In cervical smears, the panel detected SCC with 87% sensitivity and 95% specificity, and HSIL with 70% sensitivity and 94% specificity.
- The methylation markers showed differential methylation in SCC and HSIL compared to benign or low-grade lesions, with high receiver operating characteristic area under the curve (ROC AUC) values.
Conclusions:
- A 5-gene methylated DNA marker panel effectively detects SCC and HSIL in cervical smears with high accuracy.
- This molecular test can facilitate timely treatment for women with high-risk lesions and reduce unnecessary procedures for those with low-risk findings.
- Further validation in prospective studies and development of a commercial test are warranted.
