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Omics score: 15

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

ABSTRACT: Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions and chromosomal translocations. We present a model of ³looping² by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.

PROVIDER: EGAS00001000599 | EGA |

REPOSITORIES: EGA

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Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability.

Akagi Keiko K Li Jingfeng J Broutian Tatevik R TR Padilla-Nash Hesed H Xiao Weihong W Jiang Bo B Rocco James W JW Teknos Theodoros N TN Kumar Bhavna B Wangsa Danny D He Dandan D Ried Thomas T Symer David E DE Gillison Maura L ML

Genome research 20131107 2

Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of "looping" by which HPV ...[more]

PMID: 24201445

Similar Datasets

Systematic analysis of IL-1 cytokine signaling by high-risk HPV oncoproteins

Project description:Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1beta. Models of early-stage HPV infection (human keratinocytes expressing HPV16 E6 and E7) and models of established HPV-positive head and neck cancers (patient-derived xenografts, head and neck cancer cell lines) exhibited similar dysregulation of IL-1 pathway genes and suppressed responses to IL-1beta treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1beta-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.

2022-10-31 | GSE211730 | GEO

Effect of HPV 16 E6, E7 oncoproteins on the expression level of cellular genes

Project description:The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis. Primary human foreskin keratinocytes were transduced by retrovirus vectors containing HPV 16 E6, E7, E6/E7 or the control vector LXSN. The global gene expression patterns of transduced keratinocytes were analyzed on Affymetrix microarrays

2014-06-26 | E-GEOD-58841 | biostudies-arrayexpress

Effect of HPV 16 E6, E7 oncoproteins on the expression level of cellular genes

2014-06-26 | GSE58841 | GEO

A ubiquitin variant-based affinity approach selectively identifies substrates of the ubiquitin ligase E6AP in complex with HPV-11 E6 or HPV-16 E6

Project description:The E6 protein of both mucosal high risk human papillomaviruses (HPVs) such as HPV-16, which have been causally associated with malignant tumors, and low risk HPVs such as HPV-11, which cause the development of benign tumors, interacts with the cellular E3 ubiquitin ligase E6AP. This indicates that both HPV types employ E6AP to organize the cellular proteome to viral needs. However, while several substrate proteins of the high risk E6-E6AP complex are known, e.g. the tumor suppressor p53, potential substrates of the low risk E6-E6AP complex remain largely elusive. Here, we report on an affinity-based enrichment approach that enables the targeted identification of potential substrate proteins of the different E6-E6AP complexes by a combination of E3-selective ubiquitination in whole cell extracts and high-resolution mass spectrometry. The basis for the selectivity of this approach is the use of a ubiquitin variant that is efficiently used by the E6-E6AP complexes for ubiquitination, but not by E6AP alone. By this approach, we identified approximately 190 potential substrate proteins for low risk HPV-11 E6 as well as high risk HPV-16 E6. Moreover, subsequent validation experiments in vitro and within cells with selected substrate proteins demonstrate the potential of our approach. In conclusion, our data represent a reliable repository for potential substrates of the HPV-16 and HPV-11 E6 proteins in complex with E6AP.

2020-08-31 | PXD020660 | Pride

T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

Project description:Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. Researchers want to test this on human papilloma virus (HPV)-associated cancers. Objective: - The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with HPV and test the toxicity of this treatment. Eligibility: - Adults age 18-66 with an HPV-16-associated cancer. Design: * Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed * Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti HPV E6 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} * Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti HPV E6 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

| 2177506 | ecrin-mdr-crc

Long non-coding RNA FAM83H-AS1 is regulated by human papillomavirus 16 E6 independently of p53 in cervical cancer cells

Project description:Global long non-coding RNA (lncRNA) expression profile in primary human keratinocytes post-expression of high-risk HPV-16 E6 oncoprotein Purpose: The goal of this study is to utlize high-throughput RNA sequencing (RNA-seq) to identify differentially expressed host lncRNAs with the presence of the high-risk HPV-16 E6 oncoprotein in primary human foreskin keratinocytes. Methods: Primary human foreskin keratinocytes (HEKa) stably expressing HPV-16 E6 compared to GFP control were analyzed, in triplicates, by RNA-seq (Illumina). qRT-PCR validation was performed using SYBR Green assays. Results: 151 up- and 100 down-regulated host lncRNAs were altered greater than 1.5-fold change in HEKa expressing HPV-16 E6 compared to GFP control cells. Altered expression of 16 genes (8 up- and 8 down-regulated) were confirmed by qRT-PCR, demonstrating the high-degree of sensitivity of the RNA-seq method. Conclusions: Our study represents the first global screening of host lncRNAs altered specifically by HPV-16 E6 oncoprotein expression.

2018-10-31 | GSE115334 | GEO

Human Papillomavirus (HPV) genomic integration, expression and E6/E7 splicing patterns in cervical cancer associated with HPV16 or HPV18 infection

Project description:Human papillomavirus (HPV) genome integration into the host genome, blocking E2 expression and leading to overexpression of E6 and E7 viral oncogenes, is considered a major step in cervical cancer development. In high-risk HPVs, E6 and E7 oncogenes are expressed as a bicistronic pre-mRNA, with alternative splicing producing the ultimate mRNAs required for E6 and E7 translation. Given the number of alternative donor and acceptor splicing sites, ten E6/E7 different alternative transcripts might be formed for HPV16 and three for HPV18, although only six isoforms have been previously reported for HPV16. In the present work, we employ high-throughput sequencing of invasive cervical cancer transcriptome (RNA-Seq) to characterize the expression of the HPV genome in 24 invasive cervical cancers associated with HPV16 and HPV18 single infections. Based on high-resolution transcriptional maps, we herein report three viral gene expression patterns which might be associated with the presence of the viral genome in episomal and/or integrated stages. Alternative mRNAs splicing isoforms coding for E6 and E7 oncoproteins were characterized and quantified, and two novel isoforms were identified. Three major isoforms (E6*I, E6*II, and E6+E7) were detected for HPV16 and two for HPV18 (E6*I and E6+E7). Minor transcript isoforms, including the novel ones, were very rare in some tumor samples or were not detected. Our data suggested that minor transcript isoforms of E6/E7 do not play a relevant role in cervical cancer.

2019-08-06 | GSE91065 | GEO

p53-dependent R-loop formation and HPV pathogenesis

Project description:R-loops are trimeric RNA: DNA hybrids that are important physiological regulators of transcription; however, their aberrant formation or turnover leads to genomic instability and DNA breaks. High-risk human papillomaviruses are the causative agents of genital as well as oropharyngeal cancers and exhibit enhanced amounts of DNA breaks. The levels of R-loops were found to be increased up to 50-fold in cells that maintain high-risk HPV genomes and were readily detected in squamous cell cervical carcinomas in vivo but not in normal cells. The high levels of R-loops in HPV positive cells were present on both viral and cellular sites together with RNase H1, an enzyme that controls their resolution. Depletion of RNase H1 in HPV positive cells further increased R-loop levels, resulting in impaired viral transcription and replication and reduced expression of DNA repair genes such as FANCD2 and ATR, which are necessary for viral functions. Overexpression of RNase H1 decreased total R-loop levels, reducing DNA breaks by over 50%. Furthermore, increased RNase H1 expression leads to reduced R-loop levels, blocking viral transcription and replication while enhancing the expression of factors in the innate immune regulatory pathway. This suggests that maintaining elevated R-loop levels is important for the HPV life cycle. The E6 viral oncoprotein was found to be responsible for inducing high levels of R-loops by inhibiting p53’s transcriptional activity. Our studies indicate that high R-loop levels are critical for HPV pathogenesis and that this depends on suppressing the p53 pathway.

2023-08-08 | GSE240391 | GEO

Expression of miRNAs from HPV-positive penile cancer patients

Project description:PeCa is a rare carcinoma in developed countries, but it presents higher incidence rates in South America, Asia, and Africa, where limited economic and social conditions play a large impact leading to delay in diagnosis, and treatment initiation. The infection by HPV is a the risk factors and can occur through the canonical HPV/p53/RB1 pathway mediated by the E2/E6/E7 viral oncoproteins. During the transformation process, HPV inserts its genetic material into host Integration Sites (IS), affecting coding genes and miRNAs. In penile cancer (PeCa) there is limited data on the miRNAs. Considering the high frequency of HPV infection in PeCa patients in Northeast Brazil, global miRNA expression profiling was performed in high-risk HPV-associated PeCa. A panel of differentially expressed miRNAs (miRDE) was successfully constructed using 22 PeCa tissues and five non-tumor penile tissues.

2022-06-30 | GSE197121 | GEO

Expression data from N/Tert-HPV E6 cells in the presence and absence of mitomycin C treatment

Project description:HPV E6 from the genus alpha 'high risk' types such as HPV16 recruit the ubiquitin ligase E6AP to ubiquitinate p53 and target it for proteasome-mediated degradation. This results in the functional inactivation of p53 in HPV16-E6 expressing cells. To test what patterns in gene expression might change as a result of HPV16 E6 protein functions and to test whether HPV E6 proteins from genus beta virus types also inactivate p53, we profiled gene expression using Affymetrix arrays before and after stimulating p53 activity via DNA damage in a panel of N/Tert-E6 cell lines. N/Tert-1 human keratinocyte cell lines were cultured in K-SFM (Invitrogen) and treated with 2 ug/ml mitomycin C or with vehicle control for 18 hours. RNA isolated from frozen cell pellets was analyzed on Affymetrix arrays. Each cell line was grown and processed on arrays in 3-5 separate experiments.

2013-09-05 | E-GEOD-50568 | biostudies-arrayexpress

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