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Journal of Medical Virology Oct 2023
Topics: Humans; Female; Papillomavirus Infections; Uterine Cervical Neoplasms; Papillomaviridae
PubMed: 37842777
DOI: 10.1002/jmv.29177 -
Cancer Journal (Sudbury, Mass.)Human papillomavirus infection is currently implicated in the majority of oropharyngeal squamous cell carcinoma cases diagnosed in the United States. Circulating tumor... (Review)
Review
Human papillomavirus infection is currently implicated in the majority of oropharyngeal squamous cell carcinoma cases diagnosed in the United States. Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for human papillomavirus-related oropharyngeal squamous cell carcinoma and has the opportunity to improve the diagnosis, treatment, and surveillance of patients with this disease. Changes in ctDNA levels during and after primary therapy may be related to disease response, which can possibly have implications for treatment intensification or de-escalation strategies. Further, ctDNA seems to be sensitive and specific for disease recurrence and may improve upon current methods for assessing both treatment response and failure. In this review, we examine the relevant literature on the use of ctDNA for oropharyngeal cancer treatment and surveillance and discuss current limitations and future directions for this promising biomarker.
Topics: Humans; Circulating Tumor DNA; Human Papillomavirus Viruses; Squamous Cell Carcinoma of Head and Neck; Neoplasm Recurrence, Local; Oropharyngeal Neoplasms; Papillomavirus Infections; Head and Neck Neoplasms; Biomarkers; Papillomaviridae
PubMed: 37471613
DOI: 10.1097/PPO.0000000000000667 -
Journal of Medical Virology Feb 2024Regulation of human papillomavirus (HPV) gene expression is tightly linked to differentiation of the keratinocytes the virus infects. HPV late gene expression is... (Review)
Review
Regulation of human papillomavirus (HPV) gene expression is tightly linked to differentiation of the keratinocytes the virus infects. HPV late gene expression is confined to the cells in the upper layers of the epithelium where the virus capsid proteins are synthesized. As these proteins are highly immunogenic, and the upper epithelium is an immune-privileged site, this spatial restriction aids immune evasion. Many decades of work have contributed to the current understanding of how this restriction occurs at a molecular level. This review will examine what is known about late gene expression in HPV-infected lesions and will dissect the intricacies of late gene regulation. Future directions for novel antiviral approaches will be highlighted.
Topics: Humans; Animals; Human Papillomavirus Viruses; Papillomavirus Infections; Human papillomavirus 16; Cell Differentiation; Keratinocytes; Life Cycle Stages; Papillomaviridae; Virus Replication
PubMed: 38345171
DOI: 10.1002/jmv.29461 -
Microbiology Spectrum Aug 2023Infection with high-risk human papillomavirus (hrHPV) is well recognized as the main cause of cervical cancer. The recently developed Seegene Allplex HPV28 assay is a...
Comparison between the Roche Cobas 4800 Human Papillomavirus (HPV), Abbott RealTime High-Risk HPV, Seegene Anyplex II HPV28, and Novel Seegene Allplex HPV28 Assays for High-Risk HPV Detection and Genotyping in Mocked Self-Samples.
Infection with high-risk human papillomavirus (hrHPV) is well recognized as the main cause of cervical cancer. The recently developed Seegene Allplex HPV28 assay is a novel quantitative PCR (qPCR) assay designed to separately detect and quantify 28 distinct HPV genotypes in a fully automated and user-friendly manner. This study evaluated and compared the performance of this new assay with the performance of the Roche Cobas 4800, the Abbott RealTime high-risk HPV, and the Seegene Anyplex II HPV28 assays. A total of 114 mocked self-samples, i.e., semicervical samples collected by gynecologists using the Viba-Brush, were analyzed with all four HPV assays. Agreement in terms of detecting and genotyping HPV was assessed by the mean of the Cohen's kappa (κ) coefficient. Results of all four HPV assays agreed in 85.9% of the cases when using the Abbott RealTime manufacturer's recommended quantification cycle () cutoff for positivity (<32.00) and 91.2% when using an adapted range (32.00 to 36.00). An intercomparison of the included assays demonstrated an overall agreement ranging from 85.9 to 100.0% (κ = 0.42 to 1.00) when using the manufacturer's guidelines and 92.9 to 100.0% (κ = 0.60 to 1.00) with the adapted range. For all assays, highly significant, strongly positive Pearson correlations were shown between the values of positive test results. This study thereby shows high concordance between results of the included HPV assays on mocked self-samples. Based on these findings, we imply that the novel Allplex HPV28 assay demonstrates a comparable performance to those of available qPCR HPV assays, potentially providing opportunities for the simplification and standardization of future large-scale testing. This study proves that the novel Allplex HPV28 assay has a good diagnostic performance in comparison with the well-known, validated, and frequently used Roche Cobas 4800, Abbott RealTime, and Anyplex II HPV28 assays. According to our experience, the novel Allplex HPV28 assay had a user-friendly and automated workflow with short hands-on time, had an open platform which facilitates the use of add-on assays, and provided quick and easy-to-interpret results. Together with its ability to detect and quantify 28 HPV genotypes, the Allplex HPV28 assay could therefore potentially provide opportunities for the simplification and standardization of future diagnostic testing programs.
Topics: Female; Humans; Human Papillomavirus Viruses; Genotype; Papillomavirus Infections; Sensitivity and Specificity; Molecular Diagnostic Techniques; Papillomaviridae
PubMed: 37284753
DOI: 10.1128/spectrum.00081-23 -
Molecular Cell Jan 2024Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side...
Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.
Topics: Humans; Transcription Factors; Nuclear Proteins; Human Papillomavirus Viruses; Papillomavirus Infections; Proteomics; Cell Cycle Proteins; Papillomaviridae; Viral Proteins; Virus Replication; DNA Repair; Bromodomain Containing Proteins
PubMed: 38103559
DOI: 10.1016/j.molcel.2023.11.022 -
The American Journal of Surgical... Dec 2023Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We...
Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing ( P <0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P <0.001), p53 overexpression (26/42; P <0.001), and hotspot mutations in TP53 (32/42; P <0.001), CDKN2A (26/42; P <0.001) or both (21/42; P =0.003) in the adjacent SCC. Cytoplasmic p16 ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P <0.001) occurred adjacent to verrucous or papillary SCC (17/21; P <0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P <0.004). Undifferentiated p16 ink4a -negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS .
Topics: Male; Female; Humans; Papillomavirus Infections; Tumor Suppressor Protein p53; Human Papillomavirus Viruses; Skin Neoplasms; Carcinoma in Situ; Carcinoma, Squamous Cell; Penile Neoplasms; Penis; Papillomaviridae; Class I Phosphatidylinositol 3-Kinases; Vulvar Neoplasms
PubMed: 37768009
DOI: 10.1097/PAS.0000000000002130 -
International Journal of Cancer Aug 2023The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)-associated and HPV-independent squamous neoplasia with a varying cancer...
The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)-associated and HPV-independent squamous neoplasia with a varying cancer risk. Our study aimed to validate the accuracy of previously identified DNA methylation markers for detection of such high-grade vulvar intraepithelial neoplasia (VIN). A large clinical series of 751 vulvar lesions, originally diagnosed as high-grade VIN, were reassessed and categorized into HPV-associated or HPV-independent vulvar disease categories. Together with 113 healthy vulvar controls, all samples were tested for 12 methylation markers with quantitative multiplex methylation-specific PCR (qMSP). Performance of individual markers and selection of an optimal marker panel for detection of high-grade VIN was determined by logistic regression analysis. SST was the best-performing individual marker (AUC 0.90), detecting 80% of high-grade VIN cases, with excellent detection of HPV-independent VIN (95%), known to have the highest cancer risk. Merely 2% of controls tested methylation positive for SST. Selection of a marker panel, including ZNF582, SST and miR124-2, resulted in a comparably high accuracy for detection of high-grade VIN (AUC 0.89). In conclusion, we clinically validated the accuracy of 12 DNA methylation markers for detection of high-grade VIN. SST, as a sole marker or in a panel, provides an optimal diagnostic tool to distinguish high-grade VIN in need of treatment, particularly HPV-independent VIN, from low-grade or reactive vulvar lesions. These findings warrant further prognostic validation of methylation biomarkers for cancer risk stratification of patients with VIN.
Topics: Female; Humans; Papillomavirus Infections; Methylation; Papillomaviridae; Vulva; Carcinoma in Situ; Vulvar Neoplasms; Biomarkers; Human Papillomavirus Viruses
PubMed: 37074263
DOI: 10.1002/ijc.34537 -
Gynecologic Oncology Jul 2023Cervical screening has not effectively controlled cervical adenocarcinoma (AC). Human papillomavirus (HPV) testing is recommended for cervical screening but the optimal...
BACKGROUND
Cervical screening has not effectively controlled cervical adenocarcinoma (AC). Human papillomavirus (HPV) testing is recommended for cervical screening but the optimal management of HPV-positive individuals to prevent AC remains a question. Cytology and HPV typing are two triage options to predict the risk of AC. We combined two potential biomarkers (atypical glandular cell, AGC, cytology and HPV-types 16, 18, or 45) to assess their joint effect on detecting AC.
METHODS
Kaiser Permanente Northern California (KPNC) used triennial co-testing with cytology and HPV testing (positive/negative) for routine cervical screening between 2003 and 2020. HPV typing of a sample of residual HPV test specimens was performed on a separate cohort selected from KPNC (Persistence and Progression, PaP, cohort). We compared risk of prevalent and incident histologic AC/AIS (adenocarcinoma in situ) associated with preceding combinations of cytologic results and HPV typing. Risk of squamous cell cancer (SCC)/cervical intraepithelial neoplasia grade 3 (CIN3) (SCC/CIN3) was also included for comparison.
RESULTS
Among HPV-positive individuals in PaP cohort, 99% of prevalent AC and 96% of AIS were linked to HPV-types 16, 18, or 45 (denoted HPV 16/18/45). Although rare (0.09% of screening population), the concurrent detection of HPV 16/18/45 with AGC cytology predicted a highly elevated relative risk of underlying histologic AC/AIS; the absolute risk of diagnosing AC/AIS was 12% and odds ratio (OR) was 1341 (95%CI:495-3630) compared to patients with other high-risk HPV types and normal cytology. Cumulatively (allowing non-concurrent results), approximately one-third of the AC/AIS cases ever had HPV 16/18/45 and AGC cytology (OR = 1785; 95%CI:872-3656). AGC was not as strongly associated with SCC/CIN3.
CONCLUSION
Detection of HPV 16/18/45 positivity elevates risk of adenocarcinoma, particularly if AGC cytology is also found.
Topics: Female; Humans; Uterine Cervical Neoplasms; Human papillomavirus 16; Papillomavirus Infections; Early Detection of Cancer; Human papillomavirus 18; Uterine Cervical Dysplasia; Vaginal Smears; Carcinoma, Squamous Cell; Adenocarcinoma; Papillomaviridae
PubMed: 37243996
DOI: 10.1016/j.ygyno.2023.05.011 -
Modern Pathology : An Official Journal... Dec 2023p53 immunohistochemistry (IHC) has recently been shown to be a clinically useful marker for predicting risk of progression to invasive squamous cell carcinoma in oral...
p53 immunohistochemistry (IHC) has recently been shown to be a clinically useful marker for predicting risk of progression to invasive squamous cell carcinoma in oral epithelial dysplasia (OED). The literature supports the use of p53 IHC as a marker to identify TP53 mutation in in situ and invasive vulvar lesions and as a surrogate marker for high-risk human papillomavirus (HPV) infection, but there is little documentation for similar use in OED. The purpose of this study was to determine whether p53 IHC is a reliable surrogate marker for detecting both TP53 mutation and high-risk HPV infection in OED. We studied 57 cases of OED (11 mild, 18 moderate, and 28 severe), and all were stained for p16 and p53 IHC. High-risk HPV RNA in situ hybridization (ISH) was performed in selected cases (all p16-positive cases and all OED showing abundant apoptotic cells and karyorrhectic cells; N = 27). Targeted next-generation sequencing (NGS) was performed in 33 p16-negative cases and all high-risk HPV RNA ISH-negative cases (N = 36). We identified 21 cases with p53 basal sparing patterns (mid-epithelial and markedly reduced [null-like]), 14 cases with p53 wild-type patterns (scattered basal and patchy basal/parabasal), and 22 cases with p53 abnormal patterns (18 overexpression, 3 null, and 1 novel cytoplasmic pattern). Among cases with p53 basal sparing patterns, 20 were positive for p16 (20/21, 95%), and all were positive for high-risk HPV RNA ISH (21/21, 100%). The 36 sequenced cases had IHC patterns concordant with TP53 mutation status in 92% (33/36) of lesions. This study demonstrates that p53 IHC expression patterns are sensitive and specific for detection of both high-risk HPV infection and TP53 mutation. Coupled with selective p16 IHC testing, this IHC panel can accurately subclassify OED into HPV-associated, p53 wild-type (conventional), and p53 abnormal OED.
Topics: Humans; Immunohistochemistry; Human Papillomavirus Viruses; Papillomavirus Infections; Tumor Suppressor Protein p53; Biomarkers, Tumor; RNA; Cyclin-Dependent Kinase Inhibitor p16; Papillomaviridae
PubMed: 37820765
DOI: 10.1016/j.modpat.2023.100348 -
Viruses May 2024Papillomavirus gene regulation is largely post-transcriptional due to overlapping open reading frames and the use of alternative polyadenylation and alternative splicing... (Review)
Review
Papillomavirus gene regulation is largely post-transcriptional due to overlapping open reading frames and the use of alternative polyadenylation and alternative splicing to produce the full suite of viral mRNAs. These processes are controlled by a wide range of cellular RNA binding proteins (RPBs), including constitutive splicing factors and cleavage and polyadenylation machinery, but also factors that regulate these processes, for example, SR and hnRNP proteins. Like cellular RNAs, papillomavirus RNAs have been shown to bind many such proteins. The life cycle of papillomaviruses is intimately linked to differentiation of the epithelial tissues the virus infects. For example, viral late mRNAs and proteins are expressed only in the most differentiated epithelial layers to avoid recognition by the host immune response. Papillomavirus genome replication is linked to the DNA damage response and viral chromatin conformation, processes which also link to RNA processing. Challenges with respect to elucidating how RBPs regulate the viral life cycle include consideration of the orchestrated spatial aspect of viral gene expression in an infected epithelium and the epigenetic nature of the viral episomal genome. This review discusses RBPs that control viral gene expression, and how the connectivity of various nuclear processes might contribute to viral mRNA production.
Topics: RNA-Binding Proteins; Humans; Gene Expression Regulation, Viral; RNA, Viral; Papillomaviridae; Virus Replication; Viral Proteins; Papillomavirus Infections; Genome, Viral; Host-Pathogen Interactions; RNA, Messenger
PubMed: 38793664
DOI: 10.3390/v16050783