FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years

Frederique J. Vink, Chris J. L. M. Meijer, Albertus T. Hesselink, Arno N. Floore, Birgit I. Lissenberg-Witte, Jesper H. Bonde, Helle Pedersen, Kate Cuschieri, Ramya Bhatia, Mario Poljak, Anja Oštrbenk Valenčak, Peter Hillemanns, Wim G. V. Quint, Marta del Pino, Gemma G. Kenter, Renske D. M. Steenbergen, Daniëlle A. M. Heideman, Maaike C. G. Bleeker

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Abstract

BACKGROUND: High-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) grade 2/3 lesions in human papillomavirus (HPV)-positive women <30 years of age have high spontaneous regression rates. To reduce overtreatment, biomarkers are needed to delineate advanced CIN lesions that require treatment. We analyzed the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in HPV-positive women aged <30 years, aiming to identify CIN2/3 lesions in need of treatment. METHODS: A European multicenter retrospective study was designed evaluating the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in cervical scrapes of 1061 HPV-positive women aged 15-29 years (690 ≤CIN1, 166 CIN2, and 205 CIN3+). A subset of 62 CIN2 and 103 CIN3 were immunohistochemically characterized by HPV E4 expression, a marker for a productive HPV infection, and p16ink4a and Ki-67, markers indicative for a transforming infection. CIN2/3 lesions with low HPV E4 expression and high p16ink4a/Ki-67 expression were considered as nonproductive, transforming CIN, compatible with advanced CIN2/3 lesions in need of treatment. RESULTS: FAM19A4/miR124-2 methylation positivity increased significantly with CIN grade and age groups (<25, 25-29, and ≥30 years), while HPV16/18 positivity was comparable across age groups. FAM19A4/miR124-2 methylation positivity was HPV type independent. Methylation-positive CIN2/3 lesions had higher p16ink4a/Ki-67-immunoscores (P = .003) and expressed less HPV E4 (P = .033) compared with methylation-negative CIN2/3 lesions. These differences in HPV E4 and p16ink4a/Ki-67 expression were not found between HPV16/18-positive and non-16/18 HPV-positive lesions. CONCLUSIONS: Compared with HPV16/18 genotyping, the FAM19A4/miR124-2 methylation test detects nonproductive, transforming CIN2/3 lesions with high specificity in women aged <30 years, providing clinicians supportive information about the need for treatment of CIN2/3 in young HPV-positive women.

Original languageEnglish
Pages (from-to)e827-e834
JournalClinical Infectious Diseases
Volume76
Issue number3
Early online date10 Jun 2022
DOIs
Publication statusPublished - 1 Feb 2023

Keywords

  • HPV E4
  • cervical cancer
  • cervical intraepithelial neoplasia
  • host cell DNA methylation
  • human papillomavirus
  • p16 /Ki-67 immunoscore
  • p16ink4a/Ki-67 immunoscore

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