What question did this study set out to answer?

The aim was to evaluate whether methylated DNA markers can enhance sensitivity and specificity for detecting cervical lesions compared to conventional HPV testing.

April 5, 2026

Abstract 1959: The potential of methylated DNA markers for accurate detection of high-risk, HPV-positive cervical lesions.

Key Points

The aim was to evaluate whether methylated DNA markers can enhance sensitivity and specificity for detecting cervical lesions compared to conventional HPV testing.
Analyzed 222 cervical brush samples with known cytology and no histology.
Utilized a 5-gene DNA methylation assay for testing.
Employed quantitative multiplex methylation-specific PCR (QM-MSP) for detecting methylation levels.
Applied statistical analyses including ROC AUC and odds ratios.
HPV detected in 92% of HSIL and 82% of LSIL samples, indicating high sensitivity but low specificity for LSIL.
QM-MSP assay demonstrated sensitivity of 78.16% and specificity of 95.35% for distinguishing HSIL from LSIL/NEIL.
Significant differences in methylation levels between HSIL and LSIL/NIELs (P<0.0001).
In a small cohort of HPV-negative samples, high methylation was found in a portion of HSIL, suggesting potential independence from HPV status.

Abstract

Abstract Purpose: Cervical smear cytology exhibits high variability and limited sensitivity in detecting cervical lesions. While the HPV test, recommended by WHO, offers high sensitivity, it has limited specificity. Our goal was to determine whether DNA methylation markers could improve both sensitivity and specificity, thereby enabling more effective triage to colposcopy and biopsy than cytology and HPV testing. Experimental Design: We previously published a 5-gene (TBXT, MOS, FMN, EDNRB, and ZNF671) DNA methylation assay with high sensitivity and specificity for detecting cervical cancer in cytology and histology samples 1. In the current study, we tested cervical brush samples (n = 222) with known cytology but no available histology that were preserved in CytoLyt, selected and deidentified at the National Health Service screening clinic in Johannesburg, South Africa. Samples were tested for both high-risk HPV variants (Atila Biosystems) and for cumulative 5-gene methylation utilizing Quantitative Multiplex Methylation-Specific PCR (QM-MSP). Statistical tests included the Youden Index for gene-specific thresholds, odds ratio scores for individual genes, Mann-Whitney test, and Receiver Operating Characteristic Area Under the Curve (ROC AUC); a P value ≤ 0.05 was considered significant. Results: Among the 222 cervical brush samples, HPV was prevalent in similar numbers of HSIL (87/95, 92%) and LSIL (47/57, 82%), and in about half of the NIEL (39/70, 56%). Thus, HPV was highly sensitive for the detection of HSIL, but very poorly specific for low-risk LSIL or NIEL. In contrast, among HPV+ samples, to distinguish between high risk HSIL and low risk LSIL/NEIL, the QM-MSP assay showed a high level of sensitivity: 78.16% CI 68.39 - 85.55 and, in addition, a high level of specificity: 95.35% CI 88.64 - 98.18, and ROC AUC = 0.890 CI 83.71 - 94.37. A highly significant (P0.0001) difference in methylation levels was observed between HSIL and LSIL/NIELs. In the small set of HPV-negative samples, hypermethylation of the 5-gene panel was observed in 5/8 (63%) HSIL, 0/10 (0%) LSIL, and 1/31 (3%) NIEL, suggesting that QM-MSP may be independent of the HPV status. Conclusions: These findings suggest that the 5-gene panel detected a large proportion of HSIL, while the majority of LSIL and NIEL remained negative. Thus, this assay could serve as an effective triage tool for HPV+ cases, expediting care for women with HSIL while potentially reducing referrals for colposcopy in LSIL and NIEL by up to 95%. This could reduce costs and risks associated with repeated biopsy procedures for low-risk lesions. Reference: 1 DOI: 10.1186/s13148-024-01669-z Citation Format: Roshni Saravanan, Mary Jo Fackler, Madison Pleas, Wenfei Xia, Tomisin Adebari, Gang Yu, Liqun Zhang, Suzette Jordaan, Eunice Van Den Berg, Pamela Michelow, Reubina Wadee, Maureen Joffe, Wenlong Carl Chen, Youxiang Wang, Leslie Cope, Saraswati Sukumar. The potential of methylated DNA markers for accurate detection of high-risk, HPV-positive cervical lesions abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1959.

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