TY - JOUR

T1 - Detection of Cervical Lesions and Cancer in Air-Dried Cytologic Smears by Combined Analysis of mRNA and miRNA Expression Levels

AU - Ivanov, Mikhail K.

AU - Titov, Sergei E.

AU - Dzyubenko, Victoria V.

AU - Glushkov, Sergei A.

AU - Krasilnikov, Sergey E.

AU - Mansurova, Alphiya S.

AU - Malek, Anastasia V.

AU - Berlev, Igor V.

AU - Prisyazhnaya, Tatyana S.

AU - Kuleshova, Svetlana V.

AU - Hodkevich, Anastasia A.

AU - Lancuhaj, Yury A.

AU - Dimitriadi, Tatiana A.

AU - Agletdinov, Eduard F.

N1 - Funding Information: Supported by the Russian Science Foundation (project no. 20-14-00074 ). Publisher Copyright: © 2021 Association for Molecular Pathology and American Society for Investigative Pathology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5

Y1 - 2021/5

N2 - Cervical cancer screening is based on cytologic analysis and high-risk human papillomavirus (HR-HPV) testing, each having their drawbacks. Implementation of new biomarker-based methods may improve screening accuracy. Here, the levels of 25 microRNAs (miRNAs, miRs) and 12 mRNAs involved in cervical carcinogenesis in 327 air-dried Papanicolaou-stained cervical smears from patients with cervical precancerous lesions, cancer, or without the disease were estimated by real-time PCR. Using logistic regression analysis, small-scale miRNA-based, mRNA-based, and combined molecular classifiers were built based on paired ratios of miRNA or mRNA concentrations; their ability to detect high-grade cervical lesions and cancer was then compared. Combined mRNA–miRNA classifiers manifested a better combination of sensitivity and specificity than miRNA- and mRNA-based classifiers. The best classifier, combining miR-375, miR-20, miR-96, CDKN2A, TSP4, and ECM1, predicted high-grade lesions with diagnostic sensitivity of 89.0%, specificity of 84.2%, and a receiver-operating characteristic area under the curve of 0.913. Additionally, in a subsample of the same specimens, the levels of MIR124-2 and MAL promoter methylation, HR-HPV genotypes, and viral loads were analyzed. The relative high-grade lesion risk estimated by the classifier correlated with the frequency of MAL and MIR124-2 methylation but not with the HR-HPV genotype or viral load. The results support the feasibility of cellular biomarker–based methods for cervical screening and patient management.

AB - Cervical cancer screening is based on cytologic analysis and high-risk human papillomavirus (HR-HPV) testing, each having their drawbacks. Implementation of new biomarker-based methods may improve screening accuracy. Here, the levels of 25 microRNAs (miRNAs, miRs) and 12 mRNAs involved in cervical carcinogenesis in 327 air-dried Papanicolaou-stained cervical smears from patients with cervical precancerous lesions, cancer, or without the disease were estimated by real-time PCR. Using logistic regression analysis, small-scale miRNA-based, mRNA-based, and combined molecular classifiers were built based on paired ratios of miRNA or mRNA concentrations; their ability to detect high-grade cervical lesions and cancer was then compared. Combined mRNA–miRNA classifiers manifested a better combination of sensitivity and specificity than miRNA- and mRNA-based classifiers. The best classifier, combining miR-375, miR-20, miR-96, CDKN2A, TSP4, and ECM1, predicted high-grade lesions with diagnostic sensitivity of 89.0%, specificity of 84.2%, and a receiver-operating characteristic area under the curve of 0.913. Additionally, in a subsample of the same specimens, the levels of MIR124-2 and MAL promoter methylation, HR-HPV genotypes, and viral loads were analyzed. The relative high-grade lesion risk estimated by the classifier correlated with the frequency of MAL and MIR124-2 methylation but not with the HR-HPV genotype or viral load. The results support the feasibility of cellular biomarker–based methods for cervical screening and patient management.

UR - http://www.scopus.com/inward/record.url?scp=85104650166&partnerID=8YFLogxK

U2 - 10.1016/j.jmoldx.2021.01.016

DO - 10.1016/j.jmoldx.2021.01.016

M3 - Article

C2 - 33662584

AN - SCOPUS:85104650166

VL - 23

SP - 541

EP - 554

JO - Journal of Molecular Diagnostics

JF - Journal of Molecular Diagnostics

SN - 1525-1578

IS - 5

ER -