Human papillomaviruses (HPVs), which are small, double-stranded, circular DNA viruses infecting human epithelial cells, are associated with various benign and malignant lesions of mucosa and skin. ...Intensive research on the oncogenic potential of HPVs started in the 1970s and spread across Europe, including Croatia, and worldwide. Nowadays, the causative role of a subset of oncogenic or high-risk (HR) HPV types, led by HPV-16 and HPV-18, of different anogenital and head and neck cancers is well accepted. Two major viral oncoproteins, E6 and E7, are directly involved in the development of HPV-related malignancies by targeting synergistically various cellular pathways involved in the regulation of cell cycle control, apoptosis, and cell polarity control networks as well as host immune response. This review is aimed at describing the key elements in HPV-related carcinogenesis and the advances in cancer prevention with reference to past and on-going research in Croatia.
Više od 200 papilomavirusa čovjeka (HPV) inficira stanice ljudskog epitela, od kojih su alfa i beta tipovi najopsežnije proučavani i analizirani. Alfa-tipovi HPV-a primarno inficiraju epitel ...sluznice, a samo manji njihov dio povezan je s više od 600.000 karcinoma godišnje širom svijeta na različitim anatomskim mjestima, posebno anogenitalnim i regijama glave i vrata. Najvažniji karcinom uzrokovan alfa-tipovima HPV-a jest rak vrata maternice, koji je vodeći uzrok smrti povezane s rakom kod žena u mnogim dijelovima svijeta. HPV kodiraju dva onkoproteina, E6 i E7, koji izravno sudjeluju u razvoju malignosti povezanih s HPV-om. Oni djeluju u sinergiji, ciljajući različite stanične puteve koji su uključeni u regulaciju kontrole staničnog ciklusa, apoptoze i polariteta stanica. U ovom su pregledu istaknute biološke posljedice papilomavirusa koji djeluju na različite stanične proteine na različitim anatomskim mjestima u razvoju malignih tumora izazvanih HPV-om, s naglaskom na tumore glave i vrata.
Unatoč kontinuiranim naporima da se identificiraju molekularni biljezi za rano otkrivanje tumora glave i vrata (engl. HNC, head and neck cancer) te poboljšanoj terapiji, ukupno preživljenje i ...prognoza bolesnika s HNC-om i dalje su loši. Znanstveni dokazi sugeriraju da tumori povezani s HPV-om imaju bolju prognozu i preživljenje. Nadalje, epigenetičke promjene su općenito često uključene u karcinogenezu, napredovanje tumora glave i vrata te rezistenciju na terapiju. Stoga razumijevanje i karakterizacija epigenetičkih modifikacija povezanih s karcinogenezom tumora glave i vrata obećavaju identifikaciju epigenetičkih biljega za rano otkrivanje raka i poboljšanje terapijskih pristupa u borbi protiv raka. U ovom preglednom radu dan je osvrt na trenutno znanje o epigenetičkim modifikacijama, odnosno metiliranju DNA i mikroRNA uočenim kod HNC-a, posebno kod tumora orofarinksa pozitivnih na HPV.
Head and neck cancer is the sixth most common malignancy worldwide, predominantly developing from squamous cell epithelia (HNSCC). The main HNSCC risk factors are tobacco, excessive alcohol use, and ...the presence of human papillomavirus (HPV). HPV positive (+) cancers are etiologically different from other HNSCC and often show better prognosis. The current knowledge regarding HNSCC miRNA profiles is still incomplete especially in the context of HPV+ cancer. Thus, we analyzed 61 freshly collected primary oral (OSCC) and oropharyngeal (OPSCC) SCC samples. HPV DNA and RNA was found in 21% cases. The Illumina whole-genome small-RNA profiling by next-generation sequencing was done on 22 samples and revealed 7 specific miRNAs to HPV+ OSCC, 77 to HPV+ OPSCC, and additional 3 shared with both; 51 miRNAs were specific to HPV- OPSCC, 62 to HPV- OSCC, and 31 shared with both. The results for 9 miRNAs (miR-9, -21, -29a, -100, -106b, -143 and -145) were assessed by reverse transcription-quantitative polymerase chain reaction on the whole study population. The data was additionally confirmed by reanalyzing publicly available miRNA sequencing Cancer Genome Atlas consortium (TCGA) HNSCC data. Cell signaling pathway analysis revealed differences between HPV+ and HPV- HNSCC. Our findings compared with literature data revealed extensive heterogeneity of miRNA deregulation with only several miRNAs consistently affected, and miR-9 being the most likely HPV related miRNA.
The main etiological factor of precancerous lesion and invasive cervical cancer are oncogenic human papillomaviruses types (HPVs). The objective of this study was to establish the distribution of the ...most common HPVs in different cervical lesions and cancer prior to the implementation of organized population-based cervical screening and HPV vaccination in Croatia. In this study, 4,432 cervical specimens, collected through a 16-year period, were tested for the presence of HPV-DNA by polymerase chain reaction (PCR) with three sets of broad-spectrum primers and type-specific primers for most common low-risk (LR) types (HPV-6, 11) and the most common high-risk (HR) types (HPV-16, 18, 31, 33, 45, 52, 58). Additional 35 archival formalin-fixed, paraffin embedded tissue of cervical cancer specimens were analyzed using LiPA25 assay. The highest age-specific HPV-prevalence was in the group 18-24 years, which decreased continuously with age (P<0.0001) regardless of the cytological diagnosis. The prevalence of HR-HPV types significantly increased (P<0.0001) with the severity of cervical lesions. HPV-16 was the most common type found with a prevalence (with or without another HPV-type) of 6.9% in normal cytology, 15.5% in atypical squamous cells of undetermined significance, 14.4% in low-grade squamous intraepithelial lesions, 33.3% in high-grade squamous intraepithelial lesions, and 60.9% in cervical cancer specimens (P<0.0001). This study provides comprehensive and extensive data on the distribution of the most common HPV types among Croatian women, which will enable to predict and to monitor the impact of HPV-vaccination and to design effective screening strategies in Croatia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Study group included normal, neoplastic and cancer cervical samples. • Group of immune system genes were significantly hypomethylated in cancer samples. • Genes are well networked and ...related to HPV infection response. • We underscore the importance of epigenetically driven immune response.
Prognostic, diagnostic or predictive biomarkers are urgently needed for assessment of chronic graft-versus-host disease (cGvHD), a major risk for patients undergoing allogeneic hematopoietic stem ...cell transplantation. The main goal of this review generated within the COST Action EUROGRAFT "Integrated European Network on Chronic Graft Versus Host Disease" was to identify potential novel biomarkers for cGvHD besides the widely accepted molecular and cellular biomarkers. Thus, the focus was on cellular biomarkers, alloantibodies, glycomics, endothelial derived particles, extracellular vesicles, microbiome, epigenetic and neurologic changes in cGvHD patients. Both host-reactive antibodies in general, and particularly alloantibodies have been associated with cGvHD and require further consideration. Glycans attached to IgG modulate its activity and represent a promising predictive and/or stratification biomarker for cGVHD. Furthermore, epigenetic changes such as microRNAs and DNA methylation represent potential biomarkers for monitoring cGvHD patients and novel targets for developing new treatment approaches. Finally, the microbiome likely affects the pathophysiology of cGvHD; bacterial strains as well as microbial metabolites could display potential biomarkers for dysbiosis and risk for the development of cGvHD. In summary, although there are no validated biomarkers currently available for clinical use to better inform on the diagnosis, prognosis or prediction of outcome for cGvHD, many novel sources of potential markers have shown promise and warrant further investigation using well characterized, multi-center patient cohorts.
Head and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is a well known ...aetiology, which affects the nature of these cancers and patients' survival. Besides, it is considered that the main driving force for this type of cancer could be epigenetics. In this study we aimed to find potential epigenetic biomarkers, by integrating miRNome, methylome, and transcriptome analyses. From the fresh head and neck cancer tissue samples, we chose a group for miRNome, methylome and transcriptome profiling, in comparison to adequate control samples. Bioinformatics analyses are performed in R v4.2.2. Count normalisation and group differential expression for mRNA and the previously obtained miRNA count data was performed with DESeq2 v1.36. Gene set enrichment analysis was performed and visualised using gProfiler2 v0.2.1 Identification of miRNA targets was performed by querying in miRTarBase using multiMiR v1.18.0. Annotation of CpG sites merging into islands was obtained from RnBeads.hg19 v1.28.0. package. For the integrative analysis we performed kmeans clustering using stats v4.2.2 package, using 8-12 clusters and nstart 100. We found that transcriptome analysis divides samples into cancers and controls clusters, with no relation to HPV status or cancer anatomical location. Differentially expressed genes (n = 2781) were predominantly associated with signalling pathways of tumour progression. We identified a cluster of genes under the control of the transcription factor E2F that are significantly underexpressed in cancer tissue, as well as T cell immunity genes and genes related to regulation of transcription. Among overexpressed genes in tumours we found those that belong to cell cycle regulation and vasculature. A small number of genes were found significantly differentially expressed in HPV-positive versus HPV-negative tumours (for example NEFH, ZFR2, TAF7L, ZNF541, and TYMS). In this comprehensive study on an overlapping set of samples where the integration of miRNome, methylome and transcriptome analysis were performed for head and neck cancer, we demonstrated that the majority of genes were associated exclusively with miRNome or methylome and, to a lesser extent, under the control of both epigenetic mechanisms.
Head and neck cancers (HNC) are a heterogeneous group of tumours mainly associated with tobacco and alcohol use and human papillomavirus (HPV). Over 90% of all HNC are squamous cell carcinomas ...(HNSCC). Sample material from patients diagnosed with primary HNSCC (
= 76) treated with surgery as primary treatment at a single centre were assessed for HPV genotype, miR-9-5p, miR-21-3p, miR-29a-3p and miR-100-5p expression levels. Clinical and pathological data were collected from medical records. Patients were enrolled between 2015 and 2019 and followed-up until November 2022. Overall survival, disease-specific survival and disease-free survival were assessed and correlated with clinical, pathological, and molecular data. Kaplan-Meier and Cox proportional hazard regression was used to assess different risk factors. In the study, male gender, HPV-negative HNSCC (76.3%) mostly located in the oral region (78.9%) predominated. Most patients had stage IV cancer (47.4%), and the overall survival rate was 50%. HPV was found not to affect survival, indicating that in this population, classic risk factors predominate. The presence of both perineural and angioinvasion was strongly associated with survival in all analyses. Of all miRNAs assessed, only upregulation of miR-21 was consistently shown to be an independent predictor of poor prognosis and may thus serve as a prognostic biomarker in HNSCC.
The proportion of oral and oropharyngeal squamous cell carcinoma (OOSCC) that can be attributed to human papillomavirus (HPV) infection is growing nowadays. A potential factor indicating the ...occurrence of HPV-positive OSCC is a change in the degree of methylation of gene promoters that play a key role in the immune response. In this study, we investigated the difference in the methylation of
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gene promoters in samples of healthy oral mucosa versus samples of oral and oropharyngeal cancer. The presence of HPV infection in samples was examined earlier. To determine the difference in methylation of those gene promotors, isolated and bisulfite-modified DNA was analysed by the methylation-specific PCR method. The investigated gene promoters were found to be more hypomethylated in the oral and oropharyngeal cancer samples in comparison to normal tissue. The proportion of unmethylated gene promoters was similar in HPV-positive and HPV-negative cancers, although the data should be confirmed on a larger set of samples. To conclude, in samples of healthy oral mucosa, the investigated gene promoters were found to be methylated in a high percentage (73.3% to 100%), while in oral and oropharyngeal cancer samples, they were methylated in a low percentage (11.1% to 37%), regardless of HPV infection.
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