MicroRNA detection in cervical exfoliated cells as a triage for human papillomavirus-positive women

Abstract

Background: Papanicolaou (Pap) triage, with high specificity, has been recommended for primary Human papillomavirus (HPV) testing but is flawed by poor sensitivity and cytologist dependence. We evaluated the potential role of microRNA (miRNA) detection in cervical exfoliated cells in HPV-positive women from a clinic-based population.

Methods: Primary HPV testing as well as Pap test were performed on all eligible women. Six miRNAs (miR-424/miR-375/miR-34a/miR-218/miR-92a/miR-93) were detected by RT-qPCR in cervical exfoliated cells. All HPV-positive women underwent colposcopy and further biopsy if indicated. Mann-Whitney U test, the receiver operating characteristic curve, logistic regression, and Pearson's Chi-square were used to assess data. All tests of statistical significance were two-sided.

Results: A total of 1021 eligible HPV-positive women were enrolled. The expression of miR-424/miR-375/miR-34a/miR-218 in high-grade cervical intraepithelial neoplasia (CIN) and abnormal cytology was statistically significantly lower than that in low-grade CIN and normal cytology, respectively (all P < .05). Compared with the Pap test, both miR-424 and miR-375 detection achieved higher sensitivity (76.0% and 74.9% vs 63.8%, P < .05), higher negative predictive value (NPV) (85.7% and 85.4% vs 79.3%, P < .05), and comparable specificity while identifying CIN2 or worse (CIN2+). Similar results were achieved while identifying CIN3+. Multi-marker panels based on miR-424, miR-375, and miR-218 further improved the performance over any single miRNA test or Pap test.

Conclusion: Single miR-424 or miR-375 detection and miR-424/miR-375/miR-218-based multimarker panels in cervical exfoliated cells show superior performance over Pap triage for high-grade CIN identification in a clinic-based population. Detection of miRNA may provide a new triage option for HPV-positive women.

Figure 1.

Test results and outcomes. At least 1 pg/mL HPV DNA or more were identified as positive for the Digene HC2 HPV testing. Pap (+) denotes positive Pap test result and is defined as ASCUS or worse. Pap (-) denotes negative Pap test result. ASC-H = atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion; ASCUS = abnormal squamous cells of uncertain significance; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial lesion; ICC = invasive cervical cancer; LSIL = low-grade squamous intraepithelial lesion; SCC = squamous cell carcinoma.

Figure 2.

The receiver operating characteristic (ROC) curves of miRNA detection and Pap test in identifying high-grade cervical intraepithelial neoplasia (CIN). A) miRNA detection and Pap test to identify CIN2+ (CIN grade 2 or worse). B) miRNA detection and Pap test to identify CIN3+.