FAM19A4/miR124-2 methylation testing and HPV16/18 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

Research output: Contribution to journalArticle*Academicpeer-review


INTRODUCTION: HSIL or CIN2/3 lesions in HPV-positive women <30 years have high spontaneous regression rates. To reduce overtreatment, biomarkers are needed to delineate advanced CIN lesions that require treatment. We analysed the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in HPV-positive women <30 years aiming to identify CIN2/3 lesions in need of treatment.

METHODS: A European multicentre retrospective study was designed evaluating the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in cervical scrapes of 1,061 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 non-productive, 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 = 0.003) and expressed less HPV E4 (p = 0.033) 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 non-productive, transforming CIN2/3 lesions with high specificity in women <30 years, providing clinicians supportive information about the need for treatment of CIN2/3 in young HPV-positive women.

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