Dataset Information

Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix.

ABSTRACT: Although cervical intraepithelial neoplasia (CIN) is considered a neoplasia, its genomic alterations remain unknown. For this, we performed whole-exome sequencing and copy number profiling of three CINs, a microinvasive carcinoma (MIC) and four cervical squamous cell carcinomas (CSCC). Both total mutation and driver mutation numbers of the CINs were significantly fewer than those of the MIC/CSCCs (P = 0.036 and P = 0.018, respectively). Importantly, PIK3CA was altered in all MIC/CSCCs by either mutation or amplification, but not in CINs. The CINs harbored significantly lower numbers of copy number alterations (CNAs) than the MIC/CSCCs as well (P = 0.036). Pathway analysis predicted that the MIC/CSCCs were enriched with cancer-related signalings such as cell adhesion, mTOR signaling pathway and cell migration that were depleted in the CINs. The mutation-based estimation of evolutionary ages identified that CIN genomes were younger than MIC/CSCC genomes. The data indicate that CIN genomes harbor unfixed mutations in addition to human papilloma virus infection but require additional driver hits such as PIK3CA, TP53, STK11 and MAPK1 mutations for CSCC progression. Taken together, our data may explain the long latency from CIN to CSCC progression and provide useful information for molecular diagnosis of CIN and CSCC.

SUBMITTER: Jung SH

PROVIDER: S-EPMC4414197 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix.

Jung Seung-Hyun SH Choi Youn Jin YJ Kim Min Sung MS Baek In-Pyo IP Lee Sung Hak SH Lee Ah Won AW Hur Soo Young SY Kim Tae-Min TM Lee Sug Hyung SH Chung Yeun-Jun YJ

Oncotarget 20150201 6

Although cervical intraepithelial neoplasia (CIN) is considered a neoplasia, its genomic alterations remain unknown. For this, we performed whole-exome sequencing and copy number profiling of three CINs, a microinvasive carcinoma (MIC) and four cervical squamous cell carcinomas (CSCC). Both total mutation and driver mutation numbers of the CINs were significantly fewer than those of the MIC/CSCCs (P = 0.036 and P = 0.018, respectively). Importantly, PIK3CA was altered in all MIC/CSCCs by either ...[more]

PMID: 25738363

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Project description:BackgroundNQO1 (NAD(P)H: quinone oxidoreductase-1), located on chromosome 16q22, functions primarily to protect normal cells from oxidant stress and electrophilic attack. Recent studies have revealed that NQO1 is expressed at a high level in most human solid tumors including those of the colon, breast, pancreas, ovaries and thyroid, and it has also been detected following the induction of cell cycle progression and proliferation of melanoma cells. In this study, we aimed to investigate the clinicopathological significance of upregulated NQO1 protein expression in squamous cell carcinomas (SCCs) of the uterine cervix.MethodsThe localization of the NQO1 protein was determined in the SiHa cervical squamous cancer cell line using immunofluorescence (IF) staining, and immunohistochemical (IHC) staining performed on paraffin-embedded cervical SCC specimens from 177 patients. For comparison, 94 cervical intraepithelial neoplasia (CIN) and 25 normal cervical epithelia samples were also included. QRT-PCR was performed on RNA from fresh tissues to detect NQO1 mRNA expression levels, and HPV infection status was genotyped using oligonucleotide microarray. Disease-free survival (DFS) and 5-year overall survival (OS) rates for all cervical SCC patients were calculated using the Kaplan-Meier method, and univariate and multivariate analysis was performed using the Cox proportional hazards regression model.ResultsThe NQO1 protein showed a mainly cytoplasmic staining pattern in cervical cancer cells, and only three cases of cervical SCC showed a nuclear staining pattern. The strongly positive rate of NQO1 protein expression was significantly higher in cervical SCCs and CINs than in normal cervical epithelia. High-level NQO1 expression was closely associated with poor differentiation, late-stage, lymph node metastasis and high-risk for HPV infection. Additionally, high-level NQO1 expression was associated with lower DFS and 5-year OS rates, particularly for patients with early-stage cervical SCCs. Furthermore, Cox analysis revealed that NQO1 expression emerged as a significant independent hazard factor for DFS rate in patients with cervical SCC.ConclusionsNQO1 overexpression might be an independent biomarker for prognostic evaluation of cervical SCCs.

Project description:Analysis of various of up-regulated and down-regulated genes in Normal Cervical mucosa, Cervical intraepithelial neoplasia and Cervical squamous cell carcinoma. The report provides a data analysis methodology for identification of co-expressed gene patterns, as emerging clusters, in global transcriptome of cervical mucosal pre-malignant and malignant conditions in comparison to their normal counterparts. Microarray based study of global gene expression is often used to extract molecular signatures underlying cancer progression. Such endeavors endorse self organizing map, a type of artificial neural network to analyze high dimensional pre-processed transcriptome data to segregate hotspot genes in component plane for disease subtypes. This report provides a data analysis methodology for identification of coexpressed gene patterns, as emerging clusters, in global transcriptome of oral and cervical mucosal premalignant and malignant conditions in comparison to their normal counterparts. Four exclusive cluster patterns, each involving 100 − 300 genes, were identified from component planes for oral study groups. Gene expression associated with each pattern belonged to 32 biological processes. Analysis on cervical biopsies, where cancer was compared to cervical interepithelial neoplasia and normal counterpart, it revealed three non-overlapping patterns for each condition. In cervical interepithelial neoplasia an intermediate pattern with nine different dominant functional processes was identified, whereas, in cervical squamous cell carcinoma pattern showed dominance for seven different functions. This analysis demonstrated utility of self organizing map to capture dominant enriched patterns as visual plots and revealed six common biological processes like transcription and RNA processing, cytoskeleton reorganization, angiogenesis, immunity, neuron signalling, and connective tissue remodelling in the pathogenesis of oral and cervical cancers. In fact it could provide an intuitive understanding of molecular course in carcinogenesis and may contribute for combinatorial biomarker discovery.

Dataset Information

Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix.

Publications

Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix.

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