TY - JOUR
T1 - FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years
AU - Vink, Frederique J.
AU - Meijer, Chris J. L. M.
AU - Hesselink, Albertus T.
AU - Floore, Arno N.
AU - Lissenberg-Witte, Birgit I.
AU - Bonde, Jesper H.
AU - Pedersen, Helle
AU - Cuschieri, Kate
AU - Bhatia, Ramya
AU - Poljak, Mario
AU - Oštrbenk Valenčak, Anja
AU - Hillemanns, Peter
AU - Quint, Wim G. V.
AU - del Pino, Marta
AU - Kenter, Gemma G.
AU - Steenbergen, Renske D. M.
AU - Heideman, Daniëlle A. M.
AU - Bleeker, Maaike C. G.
N1 - Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - HPV E4
KW - cervical cancer
KW - cervical intraepithelial neoplasia
KW - host cell DNA methylation
KW - human papillomavirus
KW - p16 /Ki-67 immunoscore
KW - p16ink4a/Ki-67 immunoscore
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85139427358&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35686306
U2 - https://doi.org/10.1093/cid/ciac433
DO - https://doi.org/10.1093/cid/ciac433
M3 - Article
C2 - 35686306
SN - 1058-4838
VL - 76
SP - e827-e834
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 3
ER -