Analysis of HPV Integrations in Mexican Pre-Tumoral Cervical Lesions Reveal Centromere-Enriched Breakpoints and Abundant Unspecific HPV Regions

Abstract

Human papillomavirus (HPV) DNA integration is a crucial event in cervical carcinogenesis. However, scarce studies have focused on studying HPV integration (HPVint) in early-stage cervical lesions. Using HPV capture followed by sequencing, we investigated HPVint in pre-tumor cervical lesions. Employing a novel pipeline, we analyzed reads containing direct evidence of the integration breakpoint. We observed multiple HPV infections in most of the samples (92%) with a median integration rate of 0.06% relative to HPV mapped reads corresponding to two or more sequence breakages. Unlike cancer studies, most integrations events were unique (supported by one read), consistent with the lack of clonal selection. Congruent to other studies, we found that breakpoints could occur, practically, in any part of the viral genome. We noted that L1 had a higher frequency of rupture integration (25%). Based on host genome integration frequencies, we found previously reported integration sites in cancer for genes like FHIT, CSMD1, and LRP1B and putatively many new ones such as those exemplified in CSMD3, ROBO2, and SETD3. Similar host integrations regions and genes were observed in diverse HPV types within many genes and even equivalent integration positions in different samples and HPV types. Interestingly, we noted an enrichment of integrations in most centromeres, suggesting a possible mechanism where HPV exploits this structural machinery to facilitate integration. Supported by previous findings, overall, our analysis provides novel information and insights about HPVint.

Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration

“…The genomic distribution of individual integration sites is displayed in Figure 2 . A gross preference for peri-centromeric integrations were noted (see Figure 2 ) [ 43 ].…”

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…HPV integration events transpire across all human chromosomes; however, a Chinese study unveiled an excessive concentration of these events on chromosome 19 206 . Although HPV integration might seem stochastic, recent studies have pinpointed a growing array of HPV integration hotspot genes, including FHIT, LRP1B, PP1R37, HECW2, EMBP1, ANKRD50, SPTBN4, LINC00895, LYRM4‐AS1, LINC00374, RBFOX1, CSMD1, CDH13, KLHL4, KLF12, KLF5, CCDC106 207–210 . These genes may hold potential as targets for carcinogenesis and intervention.…”

The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

“…Based on this observation, actin based peptidomimetics that act as effective substrate competitive inhibitors of human SETD3 were developed [50]. These are 16-residue-long analogs of the actin peptide (66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81), in which the H73 residue is substituted by a simple natural or non-natural amino acid. Among an array of tested peptide analogs, selenomethioninecontaining actin peptide was identified as the most potent inhibitor of the human enzyme, with an IC 50 value of 0.16 µM.…”

“…An in vivo study indicated that SETD3 deficient (Setd3 −/− ) mice were viable and showed no symptoms of viral infection [63]. In the context of viral infections, the region encoding the SETD3 protein was recently shown to be an integration site in the precancerous human papillomavirus infections [79]. While only two reports are currently available regarding the importance of the SETD3 protein in viral contagiousness, it is extremely important, taking into account the current pandemic status, to investigate the role of host proteins in the progression of viral infections.…”