Abstract
Of the ~60 human papillomavirus (HPV) genotypes that infect the cervicovaginal epithelium, only 12–13 “high-risk” types are well-established as causing cervical cancer, with HPV16 accounting for over half of all cases worldwide. While HPV16 is the most important carcinogenic type, variants of HPV16 can differ in their carcinogenicity by 10-fold or more in epidemiologic studies. Strong genotype-phenotype associations embedded in the small 8-kb HPV16 genome motivate molecular studies to understand the underlying molecular mechanisms. Understanding the mechanisms of HPV genomic findings is complicated by the linkage of HPV genome variants. A panel of experts in various disciplines gathered on 21 November 2016 to discuss the interdisciplinary science of HPV oncogenesis. Here, we summarize the discussion of the complexity of the viral–host interaction and highlight important next steps for selected applied basic laboratory studies guided by epidemiological genomic findings.
Highlights
High-risk human papillomaviruses (HR-HPVs) cause a heavy burden of cancer with more than600,000 cancers attributed to HR-HPVs worldwide in 2008 [1,2,3]
To address whether even finer genetic variation (i.e., single nucleotide polymorphism (SNP)) is associated with HPV16 carcinogenicity, we evaluated non-lineage-specific SNPs and the distribution of rare variants occurring within HPV16 lineages in a collection of 5,570 HPV16-infected case-control samples [37]
Sites of integration tend to occur in regions of genomic instability [63,64,65], and have been reported to occur in short regions of HPV and host genome sequence homology (i.e., “micro-homologies”) [66,67,68], suggesting a potential role for DNA repair processes in integrating the HPV and host cell genomes based on nucleotide sequence similarities [69]
Summary
High-risk human papillomaviruses (HR-HPVs) cause a heavy burden of cancer with more than. Some HPV types within the alpha-HPVs infect mucosal epithelia and are associated with a variety of outcomes, ranging from benign asymptomatic infections to genital warts and cervical cancer. Of the ~60 alpha-HPV types, 13 from a single clade (i.e., branch of the phylogenetic tree) have been classified as definitely or probably carcinogenic (high-risk) and account for >95% of all cervical cancers worldwide. These include HPV16, HPV31, HPV33, HPV35, HPV52 and HPV58 (Alphapapillomaviruses-9 species group); HPV18, HPV39, HPV45, HPV59, and HPV68. Within each of these HPV types there are variant lineages and sublineages with intratypic genome sequence differences of 1.0–10% and 0.5–1.0%, respectively [15]. Some authors further showed that specific HPV16 lineages are associated with glandular versus squamous histology [21,26,32,34,35,36]
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