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

• Published in: Clinical infectious diseases Vol. 76; no. 3; pp. e827 - e834
• Main Authors: Vink, Frederique J, Meijer, Chris J L M, Hesselink, Albertus T, Floore, Arno N, Lissenberg-Witte, Birgit I, Bonde, Jesper H, Pedersen, Helle, Cuschieri, Kate, Bhatia, Ramya, Poljak, Mario, Oštrbenk Valenčak, Anja, Hillemanns, Peter, Quint, Wim G V, Del Pino, Marta, Kenter, Gemma G, Steenbergen, Renske D M, Heideman, Daniëlle A M, Bleeker, Maaike C G
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 08.02.2023
• Subjects: Adult; DNA Methylation; Female; Genotype; Human papillomavirus 16 - genetics; Human papillomavirus 18 - genetics; Human Papillomavirus Viruses; Humans; Ki-67 Antigen - metabolism; Major; MicroRNAs - genetics; Papillomaviridae - genetics; Papillomavirus Infections - genetics; Retrospective Studies; Uterine Cervical Dysplasia - diagnosis; Uterine Cervical Neoplasms - pathology; HPV E4; cervical cancer; p16ink4a/Ki-67 immunoscore; cervical intraepithelial neoplasia; host cell DNA methylation; human papillomavirus
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciac433

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. 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. 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. 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.