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Global Translational Medicine The research advances in HPV integration

could potentially serve as biomarkers for the diagnosis of as prognostic indicators. Combining HPV integration
CC. Assessing the methylation status of MAL and miR‑ with proteomic data identified RAB2A as a potential
124‑2 has demonstrated similar efficacy to cytological predictive biomarker for longitudinal surveillance and
tests in detecting CIN2+ in a study involving over 500 prognosis evaluation in HPV-positive patients. RAB2A
HR-HPV-positive women [82] . Another study revealed levels are significantly elevated in primary cancers
that the hypermethylation of four genes, including compared to adjacent normal tissues, and high RAB2A
hsa‑miR‑124, was meaningful for predicting precursor levels are associated with poor survival [89] .
lesions in CC [83] . As E2 is systematically disrupted during
integration, the E2/E6 mRNA ratio can provide valuable 5.3. Therapeutic options
information about the integration status. An E2/E6 ratio In addition to traditional treatments such as surgery,
below 1 is indicative of integrated viral DNA. In a study radiotherapy, and chemotherapy, an increasing number
of 248 patients diagnosed with only HPV16 infection, of clinical trials now concentrate on addressing the
it was found that an HPV16-E2/E6 ≤0.6471 or relative carcinogenic factors associated with HPV infection
levels of POU5F1B mRNA ≥1.0310 in cervical exfoliated (Table 2). Potential therapeutic methods related to
cells could reliably predict CIN2+ tumors [84] . POU5F1B virus-host interactions include knocking out integrated
is located on chromosome 8q24, a frequent site of HPV HR-HPV DNA, inhibiting early virus gene transcription,
integration. However, it is important to note that hybrid utilizing epigenetic methods (demethylation agents), and
virus-human episomes may also occur, and in such employing specific drugs targeting identified genomic
cases, the E2/E6 ratio is around 0.5, even in the absence alterations.
of integration. Thus, the E2/E6 ratio may be irrelevant if Decreasing or eliminating viral transcripts through
E2 is not the principal gene displaying integration and vaccination is a potential approach that could complement
disruption [85] . If effective biomarkers can be identified traditional chemoradiotherapy methods for HPV-
and utilized in clinical practice, it may be possible to associated tumors. Therapeutic vaccines targeting HPV
avoid invasive colposcopy in cases where the risk of CC E6/E7 have already been developed, demonstrating
is sufficiently low, indicated by low levels of molecular the ability to activate strong cytotoxic T-lymphocyte
aberrations and negative results for methylation responses . For instance, Advaxis (ADXS11-001, Advaxis
[90]
markers [38] . Inc., New Jersey, USA), expressing the HPV16-E7 antigen,
exhibits promising therapeutic efficacy . In addition,
[91]
5.2. Prognostic markers RNA-based therapies aimed at silencing E6/E7, including
Determining the physical status of HPV and identifying short-interfering RNA, CRISPR gene editing, miRNAs,
integration sites and affected genes could facilitate long non-coding RNAs, and mRNA-based HPV vaccines,
individualized patient follow-up, evaluation of disease- have also been developed.
free survival, and early clinical diagnosis of recurrent The feasibility of translating these technologies
disease. HPV-positive HNSCC generally has a more into clinically relevant modes of treatment for HPV-
favorable prognosis than HPV-negative HNSCC, and derived cancers and potentially other virus-driven
patients with integration-negative tumors exhibit better human cancers has been clinically or experimentally
survival than those with integration-positive tumors, validated [92] . In W12 20861 cells (characterized by
especially coupled with a strong HPV-specific immune tandemly repeated HPV16 integration), the use of
response [6,67] . Multiple integration events are significantly bromodomain inhibitors to displace Brd4, disrupting
associated with poor prognosis [86] . Individualized super-enhancer function, has demonstrated a decrease
tests targeting the junction between viral and cellular in the transcription of HPV16 E6/E7 and the induction
genomes, when combined with cytology, exhibit a of cellular senescence. This suggests that cancer cells
lower false positive rate for predicting recurrence harboring integrated HPV could be a potential treatment
compared to standard HPV DNA/cytology cotesting target [53] . Precision medicine is also applicable to certain
(18.2% and 12.1%, respectively). However, this strategy gene products already shown to be altered in cancer. For
lacks sensitivity, detecting integration in only 10.8% of instance, PI3K inhibitors are currently under clinical
patients [87] . Shin et al. [88] observed lower disease-free trials for treating HNSCC [12] . In CC, ERBB2 may be
survival in CC patients with completely integrated HPV activated by HPV integration in some patients, making
genomes compared to those with both integrated and them potential candidates for inclusion in clinical trials
episomal HPV, supporting the use of integration patterns of ERBB2 inhibitors [93] .

Volume 2 Issue 4 (2023) 11 https://doi.org/10.36922/gtm.2034