Genome-wide profiling of HPV integration in cervical intraepithelial neoplasia identifies enrichment of genetic elements associated with carcinogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE189452 | GEO | 2025/10/15
REPOSITORIES: GEO
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Project description:High-grade cervical intraepithelial neoplasia (CIN2/3) represents a heterogeneous disease both with respect to clinical behaviour and chromosomal aberrations detected. We hypothesized that the extent of chromosomal aberrations reflects the duration of their existence. Chromosomal profiles were determined of CIN3 of women with a known 5 year history of high-risk human papillomavirus virus (hrHPV) infection, in which duration of prior hrHPV infection was considered a proxy for duration of CIN3 existence. Eleven women had a <5 year preceding hrHPV infection (CIN3<5yrPHI) and 24 had a PHI lasting ≥5 years (CIN3≥5yrPHI). For comparison, 6 CIN3 adjacent to squamous cell carcinomas (CIN3-SCC), the corresponding SCCs, and 6 CIN1 were included. Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two clusters. One was characterized by a low number of chromosomal aberrations and included all CIN1, 81.8% of CIN3<5yrPHI and 33.3% of CIN3≥5yrPHI. Samples in the second cluster, displaying multiple aberrations, included 18.2% of CIN3<5yrPHI, 66.7% CIN3≥5yrPHI, all except one CIN3-SCC and all SCCs. The number of genomic aberrations increased according to lesion grade and also with longer duration of PHI. The increase in aberrations in CIN3≥5yrPHI compared to <5yrPHI was highly significant (p=0.001), suggesting that CIN3≥5yrPHI represent more severe lesions. A longer duration of preceding hrHPV infection is associated with an increased number of chromosomal aberrations. Hence, CIN3 with a longer duration of existence are likely more prone to have an increased short-term risk of cervical cancer.
2012-01-25 | GSE30155 | GEO
Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways. There are totally 24 clinical samples in this study comprises three stages: 7 normal cervix samples (HPV-), 9 CIN I samples (HPV+) and CIN III samples (HPV+), where normal refers to the adjacent tissue of early lesions. For each sample, its total RNA was extracted and purified, then separately hybridized to Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) and Illumina Human v2 MicroRNA Expression BeadChip, for examining the expression profiles of mRNAs and miRNAs, respectively.
2013-11-02 | E-GEOD-51993 | biostudies-arrayexpress
Project description:Genome-wide profiling of HPV integration in cervical intraepithelial neoplasia identifies enrichment of genetic elements associated with carcinogenesis
| PRJNA783039 | ENA
Project description:Offering self-sampling for HPV testing improves the effectiveness of current cervical screening programs. Molecular triage markers directly applicable on self-samples are needed to further stratify HPV-positive women at risk of cervical cancer (so-called triage) and to avoid over-referral and overtreatment. MicroRNAs (miRNAs) deregulation has been implicated in the development of cervical cancer, and represents a potential class of triage markers. However, it is unknown whether deregulated miRNA expression is reflected in self-samples. This study is the first to establish genome-wide miRNA profiles in HPV-positive self-samples to identify miRNAs that can predict the presence of CIN3 and cervical cancer in self-samples. Small RNA sequencing (sRNA-Seq) was conducted to determine genome-wide miRNA expression profiles in 73 HPV-positive self-samples of women with and without cervical precancer (CIN3). The optimal miRNA marker panel for CIN3 detection was determined by GRidge, a penalized method on logistic regression. Classification of sRNA-Seq data yielded a panel of 9 miRNAs with a combined Area Under the Curve (AUC) of 0.89 for CIN3 detection. Six out of nine miRNAs were validated by qPCR in 165 independent HPV-positive self-samples and resulted in a combined AUC of 0.72 for CIN3+ detection. This study shows that deregulated miRNA expression associated with CIN3 and cervical cancer development can be detected in HPV-positive self-samples using genome-wide miRNA profiling. Further validation by qPCR indicates that miRNA expression analysis offers a promising novel molecular triage strategy for CIN3 and cervical cancer detection applicable to self-samples.
2018-01-01 | GSE104758 | GEO
Project description:Multiple HPV genotypes infection is frequently detected in HPV+ cervical lesions, however it is not well stablished how is the different viral interaction during the carcinogenic process. Here we carried out a comprehensive study to characterize the multiple HPV genome expression and integration by RNA-Seq analysis in 19 invasive cervical carcinomas with HPV coinfections. Analysis of tumoral DNA by a hybridization kit indicated multi-infection ranging from 2 to 6 different HPV genotypes, without a preferential species coinfection. The expression analysis showed that a single HPV genotype preferentially expressed its genome, might indicating a competition between the infecting virus. Finally, the search for HPV/human chimeric transcripts indicated integration from just one HPV in almost all samples, corroborating the expression findings.
2021-07-28 | GSE144293 | GEO
Project description:Cervical cancer results from the accumulation of (epi)genetic aberrations following persistent infection with high-risk human papillomavirus (HPV). In order to define genetic aberrations associated with cervical carcinogenesis, chromosomal profiles of high-grade cervical intraepithelial neoplasia (CIN) were generated. Common aberrations usually encompass large genomic regions and contain numerous genes, hampering identification of actual driver genes. Consequently, direct evidence of chromosomal alterations actively contributing to cervical carcinogenesis has been lacking so far. By analyzing 60 high-grade CIN with high resolution arrayCGH we identified focal chromosomal aberrations that each harbour only one or a few genes. In total 74 focal aberrations were identified encoding 305 genes. Analysis of genes located within these focal aberrations, using two independent expression microarray datasets, revealed concurrent altered expression in high-grade CIN and/or cervical carcinomas compared to normal cervical samples for 8 genes: ATP13A3, HES1, OPA1, HRASLS, EYA2, ZMYND8, APOBEC2 and NCR2. Gene silencing of EYA2, located within a focal gain at 20q13, significantly reduced viability and migratory capacity of HPV16-transformed keratinocytes. Interestingly, for hsa-miR-375, located within the most frequently identified focal loss at 2q35, a direct correlation between a (focal) loss and significantly reduced expression was found. Down-regulation of hsa-miR-375 expression during cervical carcinogenesis was confirmed in a second independent series of cervical tissues. Moreover, ectopic expression of hsa-miR-375 in 2 cervical carcinoma cell lines reduced cellular viability. In conclusion, our data provide a proof of concept that chromosomal aberrations are actively contributing to HPV-induced carcinogenesis and identify EYA2 and hsa-mir-375 as oncogene and tumor suppressor gene, respectively. DNA from microdissected tissues: 60 samples total. 11 high-grade CIN, <5yr preceding hrHPV infection, 43 high-grade CIN >5yr preceding hrHPV infection, 6 CIN3 adjacent to SCC
2012-12-31 | E-GEOD-34575 | biostudies-arrayexpress
Project description:Background: Offering self-sampling of cervico-vaginal material for human papillomavirus (HPV) testing is an effective method to increase the coverage in cervical screening programmes. Molecular triage directly on HPV-positive self-samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a methylation classifier for detection of precancer (CIN3) or cancer, applicable to self-samples obtained by different devices. Findings: Genome-wide DNA methylation profiling of HPV-positive self-samples revealed 12 methylation targets for CIN3 detection. Multiplex quantitative methylation-specific PCR of these targets yielded a 3-gene methylation classifier (ASCL1, LHX8 and ST6GALNAC5), showing a very good clinical performance for CIN3 detection in both lavage (AUC=0.88; sensitivity=74%; specificity=79%) and brush (AUC=0.90; sensitivity=88%; specificity=81%) self-samples in the validation set. All self-samples from women with cervical cancer scored methylation-positive. Conclusion: By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on self-samples from HPV-positive women.
2018-01-01 | GSE99511 | GEO
Project description:The aim of this study was to identify new candidate genes that are differentially methylated in squamous cell carcinoma compared to the DNA samples from cervical intraepithelial neoplasia grade 3 (CIN3) and normal cervical scrapes. The Illumina Infinium Human Methylation 450 K BeadChip method identifies genome-wide DNA methylation changes in CpG islands, CpG shores and shelves. In this study 20 normal cervical samples (HPV negative), 18 samples with CIN3 lesions (HPV positive) and 6 cervical cancer tissues (HPV positive) were included.
2014-01-06 | E-GEOD-46306 | biostudies-arrayexpress
Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways.
2013-11-02 | GSE51993 | GEO
Project description:Human papillomaviruses (HPV) preferentially infect keratinocytes of mucous membranes or skin and cause numerous benign and malignant lesions at different anatomical locations. We sequenced small RNA (sRNA) libraries of two HPV 16 immortalized cell lines and ten formalin fixed paraffin embedded (FFPE) tissue samples from HPV infected cervical epithelium by SOLiD 4 technology.
2020-06-30 | GSE62239 | GEO