Louvanto Karolina, Verhoef Lisanne, Pimenoff Ville, Eriksson Tiina, Leppälä Siiri, Lagheden Camilla, Gray Penelope, Scibior-Bentkowska Dorota, Sumiec Elizabeth, Nieminen Pekka, Dillner Joakim, Berkhof Johannes, Meijer Chris J L M, Lehtinen Matti, Nedjai Belinda, Heideman Daniëlle A M
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.
Int J Cancer. 2024 Nov 1;155(9):1549-1557. doi: 10.1002/ijc.35044. Epub 2024 May 27.
Cervical cancer screening programs, including triage tests, need redesigning as human papillomavirus (HPV)-vaccinated women are entering the programs. Methylation markers offer a potential solution to reduce false-positive rates by identifying clinically relevant cervical lesions with progressive potential. In a nested case-control study, 9242 women who received the three-dose HPV16/18-vaccine at ages 12-15 or 18 in a community-randomized trial were included. Subsequently, they were re-randomized for either frequent or infrequent cervical cancer screening trials. Over a 15-year post-vaccination follow-up until 2022, 17 high-grade squamous intraepithelial lesion (HSIL) and 15 low-grade (LSIL) cases were identified at the 25-year screening round, alongside 371 age and community-matched HPV16/18-vaccinated controls. Methylation analyses were performed on cervical samples collected at age 25, preceding histologically confirmed LSIL or HSIL diagnoses. DNA methylation of viral (HPV16/18/31/33) and host-cell genes (EPB41L3, FAM19A4, and miR124-2) was measured, along with HPV-genotyping. No HPV16/18 HSIL cases were observed. The predominant HPV-genotypes were HPV52 (29.4%), HPV59/HPV51/HPV58 (each 23.5%), and HPV33 (17.7%). Methylation levels were generally low, with no significant differences in mean methylation levels of viral or host-cell genes between the LSIL/HSIL and controls. However, a significant difference in methylation levels was found between HSIL cases and controls when considering a combination of viral genes and EPB41L3 (p value = .0001). HPV-vaccinated women with HSIL had HPV infections with uncommon HPV types that very rarely cause cancer and displayed low methylation levels. Further investigation is warranted to understand the likely regressive nature of HSIL among HPV-vaccinated women and its implications for management.
随着接种人乳头瘤病毒（HPV）疫苗的女性开始进入宫颈癌筛查项目，包括分流检测在内的宫颈癌筛查项目需要重新设计。甲基化标志物通过识别具有进展潜力的临床相关宫颈病变，为降低假阳性率提供了一种潜在的解决方案。在一项巢式病例对照研究中，纳入了9242名在社区随机试验中于12至15岁或18岁时接种三剂HPV16/18疫苗的女性。随后，她们被重新随机分配到频繁或不频繁宫颈癌筛查试验组。在疫苗接种后长达15年的随访直至2022年期间，在25年的筛查轮次中，共确定了17例高级别鳞状上皮内病变（HSIL）和15例低级别（LSIL）病例，同时还有371名年龄和社区匹配的HPV16/18疫苗接种对照。在组织学确诊为LSIL或HSIL之前，对25岁时采集的宫颈样本进行了甲基化分析。测量了病毒（HPV16/18/31/33）和宿主细胞基因（EPB41L3、FAM19A4和miR124 - 2）的DNA甲基化情况，并进行了HPV基因分型。未观察到HPV16/18 HSIL病例。主要的HPV基因型为HPV52（29.4%）、HPV59/HPV51/HPV58（各占23.5%）和HPV33（17.7%）。甲基化水平普遍较低，LSIL/HSIL病例与对照组之间病毒或宿主细胞基因的平均甲基化水平无显著差异。然而，在考虑病毒基因和EPB41L3的组合时，HSIL病例与对照组之间的甲基化水平存在显著差异（p值 = 0.0001）。接种HPV疫苗且患有HSIL的女性感染的是罕见的HPV类型，这些类型极少引发癌症，且甲基化水平较低。有必要进一步研究，以了解接种HPV疫苗的女性中HSIL可能的消退性质及其对治疗的影响。
