Search Results (142)

Background: Effective triage of women testing positive for high-risk HPV DNA is essential to reduce unnecessary colposcopies while preserving cancer prevention. Cytology, the current standard, has limited specificity and reproducibility. The genotype-specific 7-type HPV E6/E7 mRNA test (PreTect HPV-Proofer’7), targeting HPV types 16, 18, 31, 33, 45, 52, and 58, detects transcriptionally active infections and may enhance risk stratification. Methods: Between 2019 and 2023, 34,721 women aged 25–69 underwent primary HPV DNA screening with the Cobas 4800 assay at the University Hospital of North Norway, within the national screening program. Of these, 1896 HPV DNA-positive women were triaged with liquid-based cytology with atypical squamous cells of undetermined significance or worse (≥ASC-US) and the 7-type HPV mRNA test. Histological outcomes were followed through October 2024. Diagnostic performance for CIN2+ was evaluated overall and by genotype. Results: CIN2+ prevalence was 13.3%. The mRNA test reduced test positivity from 50.3% to 33.4% while maintaining comparable sensitivity (70.6% vs. 72.2%) and improving specificity (72.3% vs. 53.0%) and PPV (28.1% vs. 19.1%). Genotype-specific PPVs were highest for HPV16 mRNA (47.7%), followed by HPV33 (39.2%) and HPV31 (32.2%), all exceeding corresponding DNA-based estimates. Conclusion: Genotype-specific HPV mRNA triage offers superior risk discrimination compared to cytology, supporting more targeted, efficient, and accessible cervical cancer screening. Full article

Human papillomavirus 18 (HPV18) is the second most oncogenic high-risk HPV genotype, after HPV16, and is responsible for about 15% of cervical cancer cases worldwide. The integration of high-risk HPV DNA into the host genome leads to the disruption of the E1 and/or E2 genes, which is considered a risk factor for viral-induced carcinogenesis. This study examined the disruption events of HPV18 E1 and E2 genes in precancerous cervical lesions to investigate the rates and sites of gene disruption in the Greek population. The complete E1 and E2 genes were amplified using three and four overlapping primer sets, respectively. Extensive analysis revealed that the disruption/deletion events of the E1 and E2 genes were detected in all grades of cytology-determined lesions, with high frequency. E2 gene disruption was significantly related to LSIL+ cases (Fisher’s exact test, p = 0.022). No significant association was found in the analysis of the E1 gene. Additionally, no preferential sites of E1/E2 gene disruption were detected. This is the first study to provide evidence of disruption events of the HPV18 E1 gene. The data from the current analysis suggest that disruption of the E2 gene could be a significant marker for the progression of cytology-determined cervical dysplasia. However, future studies are required to evaluate whether different geographic populations have particular profiles regarding the rates and sites of gene disruption to further determine population-specific biomarkers. Full article

HPV-independent cervical cancers represent a small proportion of these types of cancers, predominantly glandular lesions. It should be noted that some cases may depend on diagnostic problems that lead to false negative cases. However, the most recent classifications distinguish cervical tumors into HPV-associated and HPV-independent cancers. HPV-negative cervical carcinomas (5–11% of all cases) mainly include rare adenocarcinomas (gastric, mesonephric, clear, serous, and endometrioid) and present distinct clinical and molecular features. These tumors usually affect older women and are diagnosed at more advanced stages than HPV-positive tumors, with an overall worse prognosis. This concerning and notably worse prognosis highlights the need for further research and understanding. Unlike HPV-positive carcinomas (which depend on the viral oncogenes E6/E7), HPV-independent tumors accumulate genomic mutations that activate oncogenes and inactivate suppressor genes. Therefore, a comprehensive overview of these aspects can be the key to a better understanding and developing personalized treatments. In the present review, the main mutated genes, the signaling pathways involved, the differences from HPV-positive tumors, the distinctive immunohistochemical markers, and the diagnostic and therapeutic implications are explored in depth. Full article

Breast cancer is among the most prevalent and deadly types of cancer worldwide. Viral infections have been investigated as contributing factors in breast carcinogenesis, including infections by high-risk genotypes of human papillomavirus (HPV). Although viral DNA has been detected in breast tumors, the role of HPV activity in this type of cancer remains poorly understood. HPV oncogenes interact with various host genes, including those involved in the JAK/STAT signaling pathway. This pathway is associated with the regulation of gene expression related to the tumor microenvironment, and understanding how HPV oncogenes interact with JAK/STAT components may provide insights into the relationship between the virus and breast cancer development. In this study, we assessed the differential expression of the JAK/STAT pathway in MDA-MB-231 cells individually transfected with the E5, E6, and E7 oncogenes of HPV16. The results revealed downregulation of STAT4 in the presence of the E5, E6, and E7 oncogenes. Notably, cells transfected with E5 alone exhibited upregulation of JAK2, STAT3, and STAT6, whereas transfection with E6 and E7 resulted in their downregulation. These findings highlight the underexplored role of the E5 oncogene in contrast to the more extensively studied E6 and E7. Our results support the hypothesis that HPV oncogenes actively modulate the expression of genes involved in the tumor microenvironment in breast cancer. Full article

Background: Telomerase activity is a cancer hallmark, and hTERT is the rate-limiting catalytic subunit of telomerase. In human papillomavirus type 16 E6 (16E6)-expressing epithelial cells, NFX1-123 augments and is required for full hTERT expression, leading to a growth advantage. However, no studies have investigated the role of NFX1-123 in telomerase activity regulation in HPV-associated cancers. Methods: We knocked out NFX1-123 in CaSki cells (CaSki KO) and performed single-cell RNA sequencing to determine mRNA alterations affected by reduced NFX1-123. Results: In CaSki KO cells, there were three cell clusters based on gene expression, each associated with different enriched biological processes. When pooled and compared with control cells, CaSki KO cells had 1661 decreased and 565 increased mRNAs involving RNA regulation, cell cycle and division, chromatin regulation, and carcinogenesis processes and pathways. CENP-F, a cell cycle and chromosome segregation gene increased in cervical cancers, was among 10 genes with the greatest decrease in mRNA expression in CaSki KO cells. CaSki and SiHa cells with either reduced NFX1-123 or knocked down HPV 16 E6 and E7, demonstrated reduced hTERT, CENP-F, and telomerase activity, and when both NFX1-123 and HPV 16 E6 and E7 were decreased, hTERT and telomerase activity fell further. Finally, hTERT and CENP-F were increased in cervical cancer primary tumors and in HPV-positive head and neck cancer primary tumors in the TCGA database. Conclusions: These findings highlight the shared role that NFX1-123 has with HPV 16 oncogenes in driving and maintaining RNA, cell cycle, and carcinogenesis pathways, and specifically regulating hTERT, telomerase, and CENP-F. Full article

Cervical cancer is the second leading cause of cancer-related death in Mexico, primarily due to persistent infection with high-risk Alpha-papillomavirus genotypes, such as HPV16 and 18. Next-generation sequencing (NGS) has revealed a high prevalence of Beta- and Gamma-HPVs, mainly Beta-2 types 38b, 80, 107, and 122, in cervical cancer samples from Mexico. Our group previously reported that HPVs 38b, 107, and 122 possess transforming properties in primary fibroblasts; however, the oncogenic potential of E6/E7-HPV80 has not yet been elucidated. For this purpose, primary human fibroblasts were transduced with E6/E7-HPV80 (FB-E6/E7-HPV80), and functional assays were conducted to evaluate changes in proliferation, metabolic activity, and cell migration. RNA-seq analysis identified differentially expressed genes (DEGs) and enriched pathways. Fibroblasts transduced with E6/E7-HPV16 (FB-E6/E7-HPV16) or empty vector (FB-pLVX) served as controls. FB-E6/E7-HPV80 extended their lifespan and exhibited increased proliferation, metabolic activity, and migration capacity. RNA-seq analysis identified 196 upregulated DEGs (such as GPAT2, MST1R, ACAN, SLCO4A1, and CHRNA3) and 887 downregulated DEGs (such as KLHDC7B, TRIM58, CST1, FBLL1, INHBE, and TMEM132D) shared between FB-E6/E7-HPV80 and FB-E6/E7-HPV16. Enriched pathways included p53, TNF, IL-17, apoptosis, cell cycle, etc. These findings suggest that E6/E7-HPV80 exhibits transforming capabilities that could play an important role in cervical carcinogenesis. Full article

Cervical cancer ranks third in mortality and fourth in incidence among women worldwide as one of the leading causes of death from cancer in females. The main reason behind cervical carcinogenesis is long-term infection with high-risk human papillomavirus (HPV) genotypes, particularly HPV16 and HPV18. This review investigates HPV distribution across the world, along with cervical cancer molecular development mechanisms and current treatment strategies. Epidemiological data show that disease patterns vary significantly between different geographic regions because underdeveloped nations bear a higher disease burden. The molecular mechanisms of oncogenes E6 and E7 disrupt tumor suppressor pathways, while epigenetic modifications through DNA methylation and miRNA dysregulation promote malignant cell transformation. The reduction in HPV infection through prophylactic vaccination has shown promise, yet barriers related to accessibility and coverage still exist. The therapeutic technologies of gene expression inhibitors together with immunotherapies and epigenetic targeting agents show promise but require optimization to achieve specific targeting while minimizing off-target effects. A combined approach that integrates HPV vaccination with early diagnosis and molecular-specific therapies represents the most effective method to manage cervical cancer impact. The future care of patients will require increased translational research along with better immunization programs to drive prevention and therapeutic outcomes. Full article

The human papillomavirus (HPV) has been associated with the carcinogenesis of cutaneous squamous cell carcinoma (cSCC), especially in immunosuppressed patients. This article reviews the microbiology of HPV and its role in tissue tropism, invasion, and oncogenesis. It also describes possible HPV oncogenic ability due to the inactivation of the host p53 and retinoblastoma protein (pRb) by HPV oncoproteins E6 and E7, producing a suppression of cell cycle checkpoints and uncontrolled cell proliferation that may eventually result in invasive carcinoma. We will focus on β-HPV types and their role in epidermodysplasia verruciformis (EV), as well as α types and their ability to cause cutaneous and mucosal pathology. We also intend to examine the clinical characteristics of cSCC related to HPV and host immunosuppression conditions such as solid organ transplant in order to provide management guidelines for patients with cSCC associated with HPV based on available data. Other topics addressed in this article include particular locations of cSCC, such as nails; the prognosis; the recurrence; therapeutic modalities; and the role of HPV vaccines. Full article

The number of new cancer cases is soaring, and currently, there are 440.5 per 100,000 new cases reported every year. A quarter of these are related to human papillomavirus (HPV) infections, particularly types 16 and 18. These include oropharyngeal, anal, vaginal, and penile cancers. A critical aspect of their oncogenic potential lies in their ability to manipulate host immune responses, facilitating immune evasion and carcinogenesis. High-risk HPVs target key immune components like granzymes A and B and MHC-I, which are crucial for the elimination of virus-infected and transformed cells, thereby weakening immune surveillance. Evidence suggests that high-risk HPVs downregulate the expression of tumor suppressors, such as p53 and pRB, and the activity of these immune components, weakening CTL and NK cell responses, thus enabling persistent infection and carcinogenesis. We discuss the implications of granzyme and MHC-I dysregulation for immune evasion, tumor progression, and potential therapeutic strategies. This review further explores the regulation of granzyme A, B, and MHC-I by high-risk HPVs, focusing on how viral oncoproteins, E6 and E7, interfere with granzyme-mediated cytotoxicity and antigen presentation. The complex interplay between high-risk HPVs, granzyme A, granzyme B, and MHC-I may provide insights into novel approaches for targeting HPV-associated cancers. Full article

Human papillomavirus (HPV) is a prevalent sexually transmitted infection, implicated in various cancers, yet its influence in non-cancerous oesophageal tissue remains unclear. This study aims to investigate the gene expression changes associated with high-risk HPV (HR-HPV) in non-cancerous oesophageal tissue to elucidate potential early oncogenic mechanisms. Using RNA sequencing, we compared transcriptomic profiles of HPV-positive and HPV-negative non-cancerous oesophageal tissues. Differential gene expression analysis revealed significant upregulation of cell cycle and DNA replication pathways in HPV-positive samples, specifically involving key genes such as CCNA2, DSN1, and MCM10, which are known to regulate cellular proliferation and genomic stability. Additionally, kinase and transcription factor enrichment analyses highlighted HR-HPV-associated regulatory molecules, including E2F4 and CSNK2A1, suggesting HPV’s role in modulating host cell cycle control. These findings support the hypothesis that HPV infection may initiate cellular alterations in oesophageal tissue, potentially predisposing it to malignancy. This study contributes to understanding HPV’s impact in non-cancerous tissues and identifies possible biomarkers for early HPV-related cellular changes, offering insights into HPV-driven cancer development beyond traditionally associated sites. Full article

Persistence is a strategy used by many viruses to evade eradication by the immune system, ensuring their permanence and transmission within the host and optimizing viral fitness. During persistence, viruses can trigger various phenomena, including target organ damage, mainly due to an inflammatory state induced by infection, as well as cell proliferation and/or immortalization. In addition to immune evasion and chronic inflammation, factors contributing to viral persistence include low-level viral replication, the accumulation of viral mutants, and, most importantly, maintenance of the viral genome and reliance on viral oncoprotein production. This review focuses on the process of genome integration, which may occur at different stages of infection (e.g., HBV), during the chronic phase of infection (e.g., HPV, EBV), or as an essential part of the viral life cycle, as seen in retroviruses (HIV, HTLV-1). It also explores the close relationship between integration, persistence, and oncogenesis. Several models have been proposed to describe the genome integration process, including non-homologous recombination, looping, and microhomology models. Integration can occur either randomly or at specific genomic sites, often leading to genome destabilization. In some cases, integration results in the loss of genomic regions or impairs the regulation of oncogene and/or oncosuppressor expression, contributing to tumor development. Full article

Oncogene-induced senescence (OIS) is a form of cellular senescence triggered by oncogenic signaling and, potentially, by infection with oncogenic viruses. The role of senescence, along with its associated secretory phenotype, in the development of cervical cancer remains unclear. Additionally, the expression of the senescence-associated secretory phenotype (SASP) has not yet been explored in cervical premalignant lesions infected by the Human Papilloma Virus (HPV). This study aimed to investigate the expression of OIS and SASP markers in HPV-infected cervical precancerous lesions. We used a set of patient-derived precancerous (n = 32) and noncancerous (chronic cervicitis; n = 10) tissue samples to investigate the gene expression of several OIS (LMNB1, CDKN2A, CDKN2B, and CDKN1A), and SASP (IL1A, CCL2, TGFB1, CXCL8, and MMP9) biomarkers using qRT-PCR. OIS status was confirmed in precancerous lesions based on Lamin B1 downregulation by immunohistochemical staining. HPV status for all precancerous lesions was tested. Most of the noncancerous samples showed high Lamin B1 expression, however, precancerous lesions exhibited significant Lamin B1 downregulation (p < 0.001). Fifty-five percent of the precancerous samples were positive for HPV infection, with HPV-16 as the dominant genotype. Lamin B1 downregulation coincided with HPV E6 positive expression. CDKN2A and CDKN2B expression was higher in precancerous lesions compared to noncancerous tissue, while LMNB1 was downregulated. The SASP profile of premalignant lesions included elevated CXCL8 and TGFB1 and reduced IL1A, CCL2, and MMP9. this work shall provide an opportunity to further examine the role of OIS and the SASP in the process of malignant cervical transformation. Full article

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a potential role of the 16E5 oncoprotein in tumor development. Our previous findings indicated that 16E5 induces Fibroblast Growth Factor Receptor 2 (FGFR2) isoform switching, aberrant mesenchymal FGFR2c expression, Epithelial Mesenchymal Transition (EMT), and cell invasion in various in vitro human keratinocyte models, as well as in the in vivo context of cervical Low-grade Squamous Intraepithelial Lesions (LSILs). To further explore the role of 16E5 in epithelial carcinogenesis, this study aims to investigate the molecular profile in HPV-related anal lesions. The results showed a significant positive correlation between 16E5 and FGFR2c, as well as 16E5 or FGFR2c and key EMT-related transcription factors, particularly in the group of HPV16 positive anal samples not containing without high grade lesions. Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca²⁺ channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA. Full article

Vaccination against human papillomavirus (HPV) significantly reduces the incidence of HPV-related lesions worldwide. Considering the increasingly young age of patients in gynecological offices and earlier sexual initiation and potential contact with the HPV virus, doctors need the tools to verify diagnoses. Currently, women plan to pursue motherhood later, so it is necessary to consider whether sexual treatment in the form of, among others, loop electrosurgical excision procedures (LEEPs) may increase the risk of premature birth or difficulty dilating the cervix during labour. For this reason, to avoid the overtreatment of low-grade squamous intraepithelial lesions (LSILs), methylation testing may be considered. In patients with histopathologically confirmed high-grade squamous intraepithelial lesions (HSILs) during biopsy and, ultimately, a lower diagnosis, i.e., LSIL or no signs of atypia, methylation was found to be a useful tool. We performed a Pap smear, HPV genotyping, a punch biopsy, LEEP-conization (if needed), and methylation tests on 108 women admitted to the District Public Hospital in Poland. Women with a negative methylation test result were significantly more likely to be ultimately diagnosed with LSIL (p = 0.013). This means that in 85.7% of the patients with HSIL, major cervical surgery could be avoided if the methylation test was negative. Methylation testing, as well as dual-staining and diagnostics detecting the mRNA transcripts of highly oncogenic types of HPV, might be used in the future in the diagnosis of pre-cancerous conditions, mainly of the cervix, and in HPV-dependent cervical cancer screening. The methylation test may also be used in the diagnosis and identification of lesions within the cervical canal, including those located deep within the frontal crypts, not visible even during a professional colposcopic evaluation of the cervix. Full article