Department of Medicine, Baylor College of Medicine, Houston, Texas.
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
Cancer Prev Res (Phila). 2023 Aug 1;16(8):461-469. doi: 10.1158/1940-6207.CAPR-23-0051.
Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression.
HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.
先前的证据表明，人乳头瘤病毒（HPV）的整合状态可能与宫颈癌的发展和进展有关。然而，在病毒整合过程中可能发挥重要作用的基因中的宿主遗传变异研究较少。本研究旨在研究 HPV16 和 HPV18 病毒整合状态与宫颈癌检测光学技术两项大型试验中筛选出的 HPV16 或 HPV18 阳性的女性宫颈发育不良患者的非同源末端连接（NHEJ）DNA 修复途径基因中的 SNP 之间的关系。对 SNP 与细胞学（正常、低级别或高级别病变）之间的关系进行了评估。在患有宫颈发育不良的女性中，采用多分类逻辑回归模型来评估每个 SNP 对病毒整合状态的影响。在 710 名接受评估的女性中[149 名高级别鳞状上皮内病变（HSIL），251 名；低级别鳞状上皮内病变（LSIL），310 名正常]，395 名（55.6%）HPV16 阳性，192 名（27%）HPV18 阳性。包括 RAD50、WRN 和 XRCC4 在内的 13 个 DNA 修复基因中的标签 SNP 与宫颈发育不良显著相关。HPV16 整合状态在宫颈细胞学上存在差异，但总体而言，大多数患者既有游离型 HPV16，也有整合型 HPV16。XRCC4 基因中的 4 个标签 SNP 与 HPV16 整合状态显著相关。我们的研究结果表明，NHEJ DNA 修复途径基因，特别是 XRCC4 中的宿主遗传变异与 HPV 整合显著相关，这些基因可能在决定宫颈癌的发展和进展方面发挥重要作用。
在癌前病变中发现 HPV 整合，被认为是致癌的重要驱动因素。然而，尚不清楚是什么因素促进了整合。在出现宫颈发育不良的女性中使用靶向基因分型有可能成为评估癌症进展可能性的有效工具。
