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Reconstruction of an integrative gene regulatory meta-network reveals cell cycle and antiviral response as major drivers of cervical cancer

ABSTRACT: Cervical cancer is the one of the most common cancer type among women worldwide, with Human Papillomavirus (HPV) playing a causal role in this disease. We applied a novel integrative approach to understand the disease process and find its major drivers. We performed a meta-analysis of gene expression and chromosomal aberration studies comprising data on over 500 patients for the reconstruction of a regulatory meta-network. We found that two sub-networks representing cell cycle and antiviral response (largely involving interferon pathways) were driven by chromosomal amplifications of key regulator genes. In the majority of patients, the two types of drivers were located in the same regions of chromosomal aberrations on 3q, 1q and 1p suggesting that a synergistic effect of both processes is necessary for cervical oncogenesis. In addition, our results revealed a cause of antiviral response in the tumor supporting a model of cervical carcinogenesis in which the loss of episomal HPV mediated by immune response promotes the expression of integrated viral oncogenes and tumor progression. This series is a part of meta-analysis on gene expression in cervical cancer

ORGANISM(S): Homo sapiens

PROVIDER: GSE26342 | GEO | 2011/12/29

SECONDARY ACCESSION(S): PRJNA136923

REPOSITORIES: GEO

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Reconstruction of an integrative gene regulatory meta-network reveals cell cycle and antiviral response as major drivers of cervical cancer

Project description:Cervical cancer is the one of the most common cancer type among women worldwide, with Human Papillomavirus (HPV) playing a causal role in this disease. We applied a novel integrative approach to understand the disease process and find its major drivers. We performed a meta-analysis of gene expression and chromosomal aberration studies comprising data on over 500 patients for the reconstruction of a regulatory meta-network. We found that two sub-networks representing cell cycle and antiviral response (largely involving interferon pathways) were driven by chromosomal amplifications of key regulator genes. In the majority of patients, the two types of drivers were located in the same regions of chromosomal aberrations on 3q, 1q and 1p suggesting that a synergistic effect of both processes is necessary for cervical oncogenesis. In addition, our results revealed a cause of antiviral response in the tumor supporting a model of cervical carcinogenesis in which the loss of episomal HPV mediated by immune response promotes the expression of integrated viral oncogenes and tumor progression. This series is a part of meta-analysis on gene expression in cervical cancer Forty cervical cancer biopsies and twenty normal adjacent tissue samples were obtained from patients with cervical squamous cell carcinomas. Twelve tumor samples were hybridized as pools of two samples, due to RNA quantity limitations. So, in total, there are 34 cervical cancer and 20 normal sample arrays. We used an internal reference design, where the reference RNA sample consisted of a pool of amplified RNAs from cervical cancer biopsies.

2011-12-29 | E-GEOD-26342 | biostudies-arrayexpress

Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cells

Project description:Cervical cancer is the second most common malignancy in women worldwide, with high risk subtypes of human papillomavirus (HPV) constituting the major etiological agent. However, only a small percentage of women infected by the virus develop disease suggesting that additional host genetic alterations are necessary for disease progression. In this study we examined the genomes of a panel of commonly used model cervical cancer cell lines using a recently developed whole genome tiling path array for CGH analysis. Detailed analysis of genomic profiles enabled the detection of many novel aberrations which may have been missed by conventional cytogenetic methods. In total, 27 minimal regions of recurrent copy number alteration were identified that are potentially involved in tumorigenesis. Interestingly, fine mapping of the 3q gain, which is associated with the progression of precursor lesions to invasive cervical cancer, identified a minimal region of alteration harboring genes distinct from previous candidates. Novel regions of gene amplification, including the co-amplification of both the Birc and MMP gene clusters on 11q22, were also evident. Lastly, characterization of genomic structure at sites of HPV integration identified the copy number gain of host cellular sequences between the viral-host genomic boundaries in both SiHa and SW756, suggesting a direct role for HPV integration in the development of genetic abnormalities that initiate cervical cancer. This work represents the highest resolution look at a cervical cancer genome to date and offers definitive characterization of the alteration status of these cancer genomes. Keywords: array CGH, copy number, cervical cancer, genetic alterations, HPV integration, 3q

2007-06-12 | GSE5049 | GEO

HPV integration generates cellular super enhancer and functions as ecDNA to regulate genome-wide transcription

Project description:Human papillomavirus (HPV) integration is a critical step in cervical cancer development, while the oncogenic mechanism in genome-wide transcriptional level is still poorly understood. In this study, we employed integrative analysis on multi-omics data of cervical cancer cell lines. Through HPV integration detection, super enhancer (SE) identification, SE-associated gene expression and extrachromosomal DNA (ecDNA) investigation, we aimed to explore the genome-wide transcriptional influence of HPV integration. We identified 5 high-ranking cellular super enhancers generated by HPV integration (the HPV breakpoint induced cellular super enhancers, BP-cSE), leading to intra-chromosomal and inter-chromosomal regulations of chromosomal genes. The pathway analysis showed the dysregulated chromosomal genes were correlated to cervical cancer associated pathways. Importantly, we demonstrated that BP-cSE existed in the HPV-host ecDNA, explaining above transcription alterations. Our results suggest that HPV integration generates cellular super enhancers and functions as ecDNA to regulate unconstraint transcription, expanding the tumorigenic mechanism of HPV integration and providing insights of developing new diagnostic and therapeutic strategies.

2023-04-19 | GSE195631 | GEO

Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cells

Project description:Cervical cancer is the second most common malignancy in women worldwide, with high risk subtypes of human papillomavirus (HPV) constituting the major etiological agent. However, only a small percentage of women infected by the virus develop disease suggesting that additional host genetic alterations are necessary for disease progression. In this study we examined the genomes of a panel of commonly used model cervical cancer cell lines using a recently developed whole genome tiling path array for CGH analysis. Detailed analysis of genomic profiles enabled the detection of many novel aberrations which may have been missed by conventional cytogenetic methods. In total, 27 minimal regions of recurrent copy number alteration were identified that are potentially involved in tumorigenesis. Interestingly, fine mapping of the 3q gain, which is associated with the progression of precursor lesions to invasive cervical cancer, identified a minimal region of alteration harboring genes distinct from previous candidates. Novel regions of gene amplification, including the co-amplification of both the Birc and MMP gene clusters on 11q22, were also evident. Lastly, characterization of genomic structure at sites of HPV integration identified the copy number gain of host cellular sequences between the viral-host genomic boundaries in both SiHa and SW756, suggesting a direct role for HPV integration in the development of genetic abnormalities that initiate cervical cancer. This work represents the highest resolution look at a cervical cancer genome to date and offers definitive characterization of the alteration status of these cancer genomes. Whole genome tiling path array CGH profiles of 8 Cervical Cancer Cell Lines

2010-07-01 | E-GEOD-5049 | biostudies-arrayexpress

miRNA expression profiles of HPV-infected cervical cancer patients in the Uyghur population in China

Project description:The study examined the infection state of HPV in the Uyghur population with cervical cancer, followed by genotyping to determine the variation in the types of HPV. Using microRNA microarray technology, differential gene expression between HPV-infected cervical cancer and uninfected normal cervical tissues was determined. The microarray results were verified by qRT-PCR using 20 sets of HPV-infected cervical cancer and uninfected cervical tissues.

2016-08-27 | GSE86100 | GEO

Homo sapiens

Project description:Reconstruction of an integrative gene regulatory meta-network reveals cell cycle and antiviral response as major drivers of cervical cancer

| PRJNA136923 | ENA

Quantitative proteomic analysis of tumour tissues isolated from early and late stage human cervical cancer patients

Project description:Human papillomavirus (HPV) infection related malignancy remains a severe public health problem worldwide, although HPV prophylactic vaccine has been introduced 15 years ago . HPV-associated cancers comprise 29.1% of all 2.2 million infection-related cancers, including nearly 100% of cervical cancers1 and some head and neck cancers . Cervical cancers are the 3rd most common cancer in women worldwide, HPV16 and 18 account for about 70% of cervical cancers. Moreover, high-risk HPV infection, especially HPV16 infection, is related to a proportion of head and neck epithelial carcinoma in both developed and undeveloped countries. HPV related cancers are most severe in developing countries where HPV prophylactic vaccination rates are low.In this project, we use iTRAQ8plex-labelling proteomics to comparatively study the protein contents in the tumour tissues of early and late stage cervical cancer patietns.

2023-01-26 | PXD029103 | Pride

Spatiotemporally Deciphering the Unknown Role of Persistent HPV Infection in Precancer to Cervical Cancer Progression: Integrating Single-Cell RNA-Sequencing Landscape and Spatial Transcriptomics Atlas [scRNA-seq]

Project description:The mechanism underlying the cervical carcinogenesis mediated by persistent HPV infection remains elusive. Here we pioneeringly deciphered both temporal transition and spatial distribution of the cellular subsets during the disease progression from normal cervix, precancer lesions to cervical cancer by integrating scRNA-seq with ST. We not only identified three ‘HPV-related epithelial clusters’ unique to normal, HSIL and cervical cancer respectively, but also discovered node genes which potentially determined the disease progression. Moreover, we observed a gradual transition of multiple immune cells from positive immune response to dysregulation and exhaustion, to an immune-suppressive microenvironment during the malignant program. Besides, the cellular interaction analysis further verified a ‘homeostasis-balance-malignancy’ change within cervix microenvironment during disease escalation. Together, these findings not only deciphered mysterious persistent HPV infection spatiotemporally from the process of precancer to cervical cancer but also provided unprecedented possibilities for accurate diagnosis, precise treatment and prognosis evaluation for precancer and cervical cancer.

2023-04-02 | GSE208653 | GEO

2023-04-02 | GSE208654 | GEO

Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas

Project description:Cervical cancer develops from pre-cancerous high-grade cervical intraepithelial neoplasia (CIN) lesions harbouring a transforming infection with high-risk human papillomavirus (hrHPV), which is characterised by p16INK4a overexpression. Since it takes one or more decades for these pre-cancerous lesions to progress to invasive squamous cell carcinomas (SCCs), it is obvious that they are heterogeneous in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridisation (array CGH) of 46 p16INK4a immuno-positive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical squamous cell carcinomas (SCCs) and promoter methylation of the CADM1 gene, a tumour suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7 and 20 and losses located at 4, 11, 16, 17 and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (p=0.004). No chromosomal alterations were detected in one p16INK4a positive and five p16INK4a negative CIN1 lesions. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q and 20 are potential hallmarks of advanced p16INK4a positive CIN2/3 lesions with a high short-term risk of progression.

2009-02-20 | GSE11573 | GEO

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