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

doi:10.1093/cid/ciac433

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

25 Citations (Scopus)

58 Downloads (Pure)

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 language	English
Pages (from-to)	e827-e834
Journal	Clinical Infectious Diseases
Volume	76
Issue number	3
DOIs	https://doi.org/10.1093/cid/ciac433
Publication status	Published - 1-Feb-2023
Externally published	Yes

Keywords

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

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Vink, F. J., Meijer, C. J. L. M., Hesselink, A. T., Floore, A. N., Lissenberg-Witte, B. I., Bonde, J. H., Pedersen, H., Cuschieri, K., Bhatia, R., Poljak, M., Oštrbenk Valenčak, A., Hillemanns, P., Quint, W. G. V., del Pino, M., Kenter, G. G., Steenbergen, R. D. M., Heideman, D. A. M., & Bleeker, M. C. G. (2023). FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years. Clinical Infectious Diseases, 76(3), e827-e834. https://doi.org/10.1093/cid/ciac433

@article{7488f736961249c3a0839f1e1d797f6d,

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

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.",

keywords = "HPV E4, cervical cancer, cervical intraepithelial neoplasia, host cell DNA methylation, human papillomavirus, p16ink4a/Ki-67 immunoscore, p16 /Ki-67 immunoscore",

author = "Vink, \{Frederique J.\} and Meijer, \{Chris J. L. M.\} and Hesselink, \{Albertus T.\} and Floore, \{Arno N.\} and Lissenberg-Witte, \{Birgit I.\} and Bonde, \{Jesper H.\} and Helle Pedersen and Kate Cuschieri and Ramya Bhatia and Mario Poljak and \{O{\v s}trbenk Valen{\v c}ak\}, Anja and Peter Hillemanns and Quint, \{Wim G. V.\} and \{del Pino\}, Marta and Kenter, \{Gemma G.\} and Steenbergen, \{Renske D. M.\} and Heideman, \{Dani{\"e}lle A. M.\} and Bleeker, \{Maaike C. G.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Oxford University Press on behalf of the Infectious Diseases Society of America.",

year = "2023",

month = feb,

day = "1",

doi = "10.1093/cid/ciac433",

language = "English",

volume = "76",

pages = "e827--e834",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "3",

}

Vink, FJ, Meijer, CJLM, Hesselink, AT, Floore, AN, Lissenberg-Witte, BI, Bonde, JH, Pedersen, H, Cuschieri, K, Bhatia, R, Poljak, M, Oštrbenk Valenčak, A, Hillemanns, P, Quint, WGV, del Pino, M, Kenter, GG, Steenbergen, RDM, Heideman, DAM & Bleeker, MCG 2023, 'FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years', Clinical Infectious Diseases, vol. 76, no. 3, pp. e827-e834. https://doi.org/10.1093/cid/ciac433

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 - p16ink4a/Ki-67 immunoscore

KW - p16 /Ki-67 immunoscore

U2 - 10.1093/cid/ciac433

DO - 10.1093/cid/ciac433

M3 - Article

SN - 1058-4838

VL - 76

SP - e827-e834

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 3

ER -

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

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Keywords

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