Phylogenomic Analysis of Human Papillomavirus Type 31 and Cervical Carcinogenesis: A Study of 2093 Viral Genomes

Abstract

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.

Human papillomaviruses: Knowns, mysteries, and unchartered territories

“…These are important components of the host cell's arsenal of defense mechanisms and function as potent mutagens and garble the infecting pathogen's genetic information 104 . Unlike many other pathogens, HPVs do not appear to mute this cellular defense response, 105 and many of the HPV16 variants detected in this study are consistent with APOBEC3 activity 100,101 . Those mutations that do not follow the APOBEC mutational signature may have arisen due to replication errors.…”

“…When Mirabello and colleagues sequenced HPV16 genomes from HPV16‐infected individuals, they detected an astonishing number of sequence variants 100 . A subsequent large‐scale sequencing study of HPV31‐infected individuals yielded similar results 101 . HPV31 is a high‐risk HPV 102 and like HPV16 is a member of the alpha 9 species.…”

“…Some of the nucleotide changes present in these variants result in alterations of the coding sequence of the viral ORFs, including E6 and, remarkably to a far lesser extent, E7 100,101 . It will be interesting to determine whether some of these variants may be more or less carcinogenic 109 and whether the presence of a specific variant may predict an increased or decreased risk for malignant progression.…”

“…and, remarkably to a far lesser extent, E7. 100,101 It will be interesting to determine whether some of these variants may be more or less carcinogenic 109 and whether the presence of a specific variant may T A B L E 2 Animal PVs that do not encode E6 and/or E7 proteins. (Continues) predict an increased or decreased risk for malignant progression.…”

Distinguishing Genetic Drift from Selection in Papillomavirus Evolution

“…Viruses 2023, 15, 1631 2 of 18 in papillomavirus genomes [29,30]. Indeed, elevated oncogenic risk from large epidemiological studies is also associated with variations in non-coding regions and with silent substitutions that are non-randomly distributed across the ~8000 bp genome [30][31][32][33].…”