Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Natalia Shulzhenko

PROVIDER: E-GEOD-26342 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

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

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