Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Pathology, Amsterdam, the Netherlands.
Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Clin Infect Dis. 2023 Feb 8;76(3):e827-e834. 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.
人乳头瘤病毒（HPV）阳性且年龄<30 岁的女性中，高级别鳞状上皮内病变（HSIL）或宫颈上皮内瘤变（CIN）2/3 级病变有较高的自发消退率。为了减少过度治疗，需要生物标志物来区分需要治疗的高级别 CIN 病变。本研究旨在分析 HPV 阳性且年龄<30 岁的女性中 FAM19A4/miR124-2 甲基化检测和 HPV16/18 基因分型，以确定需要治疗的 CIN2/3 病变。
这是一项欧洲多中心回顾性研究，评估了 1061 例年龄 15-29 岁的 HPV 阳性女性（690 例 CIN1、166 例 CIN2 和 205 例 CIN3+）的 FAM19A4/miR124-2 甲基化检测和 HPV16/18 基因分型。62 例 CIN2 和 103 例 CIN3 的亚组通过 HPV E4 表达（一种有活性 HPV 感染的标志物）和 p16ink4a、Ki-67 进行免疫组织化学特征分析，这两个标志物提示转化性感染。HPV E4 表达低和 p16ink4a/Ki-67 表达高的 CIN2/3 病变被认为是非产性、转化性 CIN，与需要治疗的高级别 CIN2/3 病变相符。
随着 CIN 分级和年龄组（<25、25-29 和≥30 岁）的增加，FAM19A4/miR124-2 甲基化阳性率显著增加，而 HPV16/18 阳性率在年龄组间无差异。FAM19A4/miR124-2 甲基化阳性与 HPV 类型无关。与甲基化阴性的 CIN2/3 病变相比，甲基化阳性的 CIN2/3 病变的 p16ink4a/Ki-67-免疫评分更高（P=0.003），HPV E4 表达更低（P=0.033）。HPV16/18 阳性和非 16/18 HPV 阳性病变之间未发现 HPV E4 和 p16ink4a/Ki-67 表达的这些差异。
与 HPV16/18 基因分型相比，FAM19A4/miR124-2 甲基化检测在年龄<30 岁的女性中可特异性检测非产性、转化性 CIN2/3 病变，为年轻 HPV 阳性女性的 CIN2/3 治疗提供临床支持信息。
