Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA.
Departments of Pediatrics and Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Viruses. 2021 Sep 28;13(10):1948. doi: 10.3390/v13101948.
Human papillomavirus (HPV) type 31 (HPV31) is closely related to the most carcinogenic type, HPV16, but only accounts for 4% of cervical cancer cases worldwide. Viral genetic and epigenetic variations have been associated with carcinogenesis for other high-risk HPV types, but little is known about HPV31. We sequenced 2093 HPV31 viral whole genomes from two large studies, one from the U.S. and one international. In addition, we investigated CpG methylation in a subset of 175 samples. We evaluated the association of HPV31 lineages/sublineages, single nucleotide polymorphisms (SNPs) and viral methylation with cervical carcinogenesis. HPV31 A/B clade was >1.8-fold more associated with cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) compared to the most common C lineage. Lineage/sublineage distribution varied by race/ethnicity and geographic region. A viral genome-wide association analysis identified SNPs within the A/B clade associated with CIN3+, including H23Y (C626T) (odds ratio = 1.60, confidence intervals = 1.17-2.19) located in the pRb CR2 binding-site within the E7 oncogene. Viral CpG methylation was higher in lineage B, compared to the other lineages, and was most elevated in CIN3+. In conclusion, these data support the increased oncogenicity of the A/B lineages and suggest variation of E7 as a contributing risk factor.
人乳头瘤病毒（HPV）31 型（HPV31）与最具致癌性的 HPV16 型密切相关，但仅占全球宫颈癌病例的 4%。病毒遗传和表观遗传变异与其他高危型 HPV 的致癌作用有关，但对 HPV31 知之甚少。我们对来自两项大型研究的 2093 个 HPV31 病毒全基因组进行了测序，其中一项来自美国，一项来自国际。此外，我们还调查了 175 个样本中的 CpG 甲基化情况。我们评估了 HPV31 谱系/亚谱系、单核苷酸多态性（SNP）和病毒甲基化与宫颈癌发生的关系。HPV31 A/B 分支与宫颈上皮内瘤变 3 级和癌症（CIN3+）的相关性是最常见的 C 分支的 1.8 倍以上。谱系/亚谱系分布因种族/民族和地理位置而异。一项病毒全基因组关联分析确定了 A/B 分支中与 CIN3+相关的 SNP，包括位于 E7 癌基因 pRb CR2 结合位点内的 H23Y（C626T）（比值比=1.60，置信区间=1.17-2.19）。与其他谱系相比，B 谱系的病毒 CpG 甲基化水平更高，在 CIN3+中最高。总之，这些数据支持 A/B 谱系的致癌性增加，并表明 E7 的变异是一个致病风险因素。
