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

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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 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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FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 YearsFinal publisher's version, 674 KBLicence: CC BY-NC-ND

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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 = "BackgroundHigh-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.MethodsA 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.ResultsFAM19A4/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.ConclusionsCompared 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 - BackgroundHigh-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.MethodsA 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.ResultsFAM19A4/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.ConclusionsCompared 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 - BackgroundHigh-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.MethodsA 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.ResultsFAM19A4/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.ConclusionsCompared 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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