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Global Translational Medicine The research advances in HPV integration

stands out as the main infectious oncogenic pathogen, regulatory control over the immune microenvironment [9,10] .
accounting for over 50% of infection-related cancers . In the context of cervical carcinogenesis, the integration
[2]
The identification of over 200 distinct HPV types has been of the extrachromosomal viral genome into the host
a significant advancement in understanding this complex chromosome emerges as a common occurrence. Notably,
viral landscape. At present, 231 HPV reference types in cervical cancer, HPV integration events can be detected
have been cataloged and submitted to the International in premalignant lesions, with the percentage of cells
HPV Reference Center (https://www.hpvcenter.se/ containing integrated HPV genome escalating with disease
[11]
human_reference_clones/). Five genera of HPV have progression . The integration event is, therefore, thought
been defined: Alphapapillomavirus, Betapapillomavirus, to transpire at a later stage in the progression of high-grade
[12]
Gammapapillomavirus, Mupapillomavirus, and cervical dysplasia . In cervical cancer cases, approximately
Nupapillomavirus. The alpha genus is particularly well- 70% of HPV16-positive cases and almost all HPV18-
characterized, as a subset of these mucosal viruses has been associated cases exhibit detectable viral integration [5,13] .
classified as “high-risk” or carcinogenic. The World Health Similarly, about 75% of HPV16-associated oropharyngeal
Organization (WHO) identifies at least 12 genotypes of squamous cell carcinomas (OPSCC) and uterine cervical
HPV (genotype 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, squamous cell carcinoma (UCSCC) display viral genome
and 59) as high-risk, with HPV16 and 18 being the most integration [14,15] . The significance of HPV integration
prevalent high-risk HPVs (HR-HPVs) worldwide . is underscored by its potential utility as a biomarker for
[3]
Among the numerous HPV types, 20 display a notably diagnosis, prognostic monitoring, survival prediction, and
higher prevalence in cases of cervical cancer when even in HPV-related cancer screening. Consequently, the
compared to women with normal cervical cytology. All integration status of HR-HPV has become a focal point
HPVs infect epithelial cells, usually through the mucosal in the realm of early diagnosis and precision treatment of
or cutaneous route. HR-HPVs are associated with various cervical lesions.
human mucosal surface cancers, including penile, vulvar, It has been suggested that integration may confer a
vaginal, anal, oropharyngeal, and cervical cancers (CC) . selective growth advantage to the virus and trigger host
[4]
Notably, it has been suggested that at least 90% of CC and cell transformation through dysregulation of E6/E7
over 70% of oropharyngeal cancers are associated with viral oncogenes, resulting in an imbalance between cell
HR-HPV infection [5,6] . proliferation and apoptosis and an increase in genetic
HPVs are non-enveloped, double-stranded circular DNA instability [11,12] . However, it is crucial to recognize that
viruses characterized by a 7 – 8 kb genome comprising three E6/E7 overexpression is not the sole factor underlying
carcinogenesis. A series of structural and epigenetic
distinct regions: The upstream regulatory region (URR), changes in the host genome, resulting from viral genome
the early coding region (E), and the late coding region (L). integration, may also play an important role. Much remains
Within the beta genus, HPVs lack the E5 open reading to be elucidated about the mechanisms of integration
frame (ORF), and the size or position of ORFs can vary. and the ensuing patterns and alterations to the human
However, HPVs generally contain highly conserved regions genome. In this review, we will briefly describe the current
for replication (E1 and E2) and packaging (L1 and L2), with understanding of the mechanism of HPV integration,
other genes displaying greater sequence diversity between the role of HPV in the neoplastic transformation and
[5]
genotypes . E4 is thought to influence tropism and may carcinogenesis process, recent advances in the detection and
affect virus release or transmission . In the alpha genus, analysis of HPV integration, and the clinical significance
[7]
the E5, E6, and E7 proteins serve as accessory proteins of HPV integration in cancer prediction, prognostic
supporting the HPV life cycle. They manipulate the balance evaluation, and the treatment for HPV-associated disease.
of cell proliferation and differentiation while antagonizing
innate immune pathways . The E6 and E7 proteins of 2. Mechanism of HPV integration
[8]
HR-HPVs interact with numerous proteins involved in cell Little is currently understood about the mechanism
cycle regulation, including p53 and pRB.
through which the HPV genome integrates into the host
Persistent HPV infection is associated with cancer genome. However, it is evident that this integration is
development, yet the precise mechanisms through which an active process within the virus life cycle rather than
HPV induces carcinogenesis remain unclear. A critical an incidental or arbitrary occurrence. HPV integration
oncogenic step involves the escape of HPV from immune exhibits a propensity to take place at random points
system clearance and detection. Different proportions throughout the human genome, with a notable preference
of T-helper (Th) cells, including Th17 cells, have been for regions proximate to CpG sites, transcriptionally
identified in different cervical lesion grades, exerting active regions, and common fragile sites . It has been
[16]

Volume 2 Issue 4 (2023) 2 https://doi.org/10.36922/gtm.2034