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Int J Cancer. 2019 Jan 1;144(1):160-168. doi: 10.1002/ijc.31787. Epub 2018 Nov 18.

Reliable identification of women with CIN3+ using hrHPV genotyping and methylation markers in a cytology-screened referral population.

Author information

1
DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
2
Institute of Gynecology, Obstetrics and Neonatology, Hospital Clínic -Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Faculty of Medicine-University of Barcelona, Barcelona, Spain.
3
Department of Pathology, ISGlobal, Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain.
4
Roosevelt Kliniek, Department of Pathology, Leiden, The Netherlands.
5
Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands.
6
Erasmus MC University Medical Center, Department of Pathology, Rotterdam, The Netherlands.

Abstract

Cervical screening aims to identify women with high-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia 2-3 (HSIL/CIN2-3) or invasive cervical cancer (ICC). Identification of women with severe premalignant lesions or ICC (CIN3+) could ensure their rapid treatment and prevent overtreatment. We investigated high-risk human papillomavirus (hrHPV) detection with genotyping and methylation of FAM19A4/miR124-2 for detection of CIN3+ in 538 women attending colposcopy for abnormal cytology. All women had an additional cytology with hrHPV testing (GP5+/6+-PCR-EIA+), genotyping (HPV16/18, HPV16/18/31/45), and methylation analysis (FAM19A4/miR124-2) and at least one biopsy. CIN3+ detection was studied overall and in women <30 (n = 171) and ≥30 years (n = 367). Positivity for both rather than just one methylation markers increased in CIN3, and all ICC was positive for both. Overall sensitivity and specificity for CIN3+ were, respectively, 90.3% (95%CI 81.3-95.2) and 31.8% (95%CI 27.7-36.1) for hrHPV, 77.8% (95%CI 66.9-85.8) and 69.3% (95%CI 65.0-73.3) for methylation biomarkers and 93.1% (95%CI 84.8-97.0) and 49.4% (95%CI 44.8-53.9) for combined HPV16/18 and/or methylation positivity. For CIN3, hrHPV was found in 90.9% (95%CI 81.6-95.8), methylation positivity in 75.8% (95%CI 64.2-84.5) and HPV16/18 and/or methylation positivity in 92.4% (95%CI 83.5-96.7). In women aged ≥30, the sensitivity of combined HPV16/18 and methylation was increased (98.2%, 95%CI 90.6-99.7) with a specificity of 46.3% (95%CI 40.8-51.9). Combination of HPV16/18 and methylation analysis was very sensitive and offered improved specificity for CIN3+, opening the possibility of rapid treatment for these women and follow-up for women with potentially regressive, less advanced, HSIL/CIN2 lesions.

KEYWORDS:

FAM19A4; Triage; cervical cancer; human papillomavirus; intraepithelial neoplasia; miR124-2

PMID:
30098013
PMCID:
PMC6587551
DOI:
10.1002/ijc.31787
[Indexed for MEDLINE]
Free PMC Article

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