Detection of high-grade neoplasia in air-dried cervical PAP smears by a microRNA-based classifier

Recent studies have shown that changes in the expression levels of certain microRNAs correlate with the degree of severity of cervical lesions. The aim of the present study was to develop a microRNA-based classifier for the detection of high-grade cervical intraepithelial neoplasia (CIN ≥2) in cytol...

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Bibliographic Details
Published in:	Oncology reports Vol. 39; no. 3; pp. 1099 - 1111
Main Authors:	Ivanov, Mikhail K, Titov, Sergei E, Glushkov, Sergei A, Dzyubenko, Victoria V, Malek, Anastasia V, Arkhangelskaya, Polina A, Samsonov, Roman B, Mikhetko, Andrey A, Bakhidze, Elena V, Berlev, Igor V, Kolesnikov, Nikolay N
Format:	Journal Article
Language:	English
Published:	Greece Spandidos Publications 01-03-2018 Spandidos Publications UK Ltd D.A. Spandidos
Subjects:	Adult Biomarkers Biomarkers, Tumor - genetics Care and treatment Case-Control Studies Cellular biology Cervical cancer Cervical Intraepithelial Neoplasia - classification Cervical Intraepithelial Neoplasia - diagnosis Cervical Intraepithelial Neoplasia - genetics Cervical Intraepithelial Neoplasia - virology Cervix Uteri - pathology Cervix Uteri - virology Clinical medicine Deoxyribonucleic acid Diagnosis DNA DNA methylation DNA, Viral Female Follow-Up Studies Human papillomavirus Humans Infections Medical screening Methods MicroRNAs MicroRNAs - genetics Pap smear Pap test Papanicolaou Test - methods Papillomaviridae - genetics Papillomavirus Infections - complications Papillomavirus Infections - epidemiology Papillomavirus Infections - virology Patient outcomes Prognosis ROC Curve Squamous Intraepithelial Lesions of the Cervix - classification Squamous Intraepithelial Lesions of the Cervix - diagnosis Squamous Intraepithelial Lesions of the Cervix - genetics Squamous Intraepithelial Lesions of the Cervix - virology Studies Uterine Cervical Neoplasms - classification Uterine Cervical Neoplasms - diagnosis Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - virology Vaginal Smears Viral Load
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Summary:	Recent studies have shown that changes in the expression levels of certain microRNAs correlate with the degree of severity of cervical lesions. The aim of the present study was to develop a microRNA-based classifier for the detection of high-grade cervical intraepithelial neoplasia (CIN ≥2) in cytological samples from patients with different high-risk human papillomavirus (HR-HPV) viral loads. For this purpose, raw RT-qPCR data for 25 candidate microRNAs, U6 snRNA and human DNA in air-dried PAP smears from 174 women with different cervical cytological diagnoses, 144 of which were HR-HPV-positive [40 negative for intraepithelial lesion or malignancy (NILM), 34 low-grade squamous intraepithelial lesions (L-SIL), 57 high-grade squamous intraepithelial lesions (H-SIL), 43 invasive cancers], were statistically processed. The expression level changes of various individual microRNAs were found to be significantly correlated with the cytological diagnosis but the statistical significance of this correlation was critically dependent on the normalization strategy. We developed a linear classifier based on the paired ratios of 8 microRNA concentrations and cellular DNA content. The classifier determines the dimensionless coefficient (DF value), which increases with the severity of cervical lesion. The high- and low-grade CINs were better distinguished by the microRNA classifier than by the measurement of individual microRNA levels with the use of traditional normalization methods. The diagnostic sensitivity of detecting high-grade lesions (CIN ≥2) with the developed microRNA classifier was 83.4%, diagnostic specificity 81.2%, ROC AUC=0.913. The analysis can be performed with the same nucleic acid preparation as used for HPV testing. No statistically significant correlation of the DF value and HR-HPV DNA load was found. The DF value and the HR HPV presence and viral DNA load may be regarded as independent criteria that can complement each other in molecular screening for high-grade cervical intraepithelial neoplasia. Although it has several limitations, the present study showed that the small-scale analysis of microRNA signatures performed by simple PCR-based methods may be useful for improving the diagnostic/prognostic value of cervical screening.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1021-335X 1791-2431
DOI:	10.3892/or.2018.6214