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HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

ABSTRACT: Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Cancer Genome Atlas (TCGA) was used to determine correlates of 5-year survival, using regression tree-based optimal threshold calculations. Survival-associated gene sets were transformed to gene set scores that were assessed for correlation with clinicopathological data. We identified 8 gene co-expression modules for HNSCC tumors, each of which contained co-expressed genes associated significantly with 5-year survival. Survival-associated co-expression gene signatures correlated dominantly with tumor HPV and p16 status. Network analysis identified that survival was associated with signaling networks of infection, immunity, epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, focal adhesion, extracellular matrix, MYC signaling, autophagy and transcriptional regulation. EMT-associated gene signatures were expressed dominantly in fibroblasts, and cancer-associated fibroblasts were inversely correlated with immune activity. Interestingly, a high Immune Suppression Score based on expression of 21 genes associated with immune inhibition and including immune checkpoints, cytokines and regulatory T cell factors, was also associated with increased survival probability, and was significantly higher in HPV+ HNSCC. Networks associated with HNSCC survival were further associated with survival in cervical cancer, melanoma and lung cancer. This study defines 5129 genes associated with HNSCC survival, organized into co-expressed networks, their correlation with clinicopathological data, and with gene expression data from other malignant diseases, and provides a source for the discovery of biomarkers and novel therapies for HNSCC.

SUBMITTER: Mehdi AM

PROVIDER: S-EPMC10104777 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

Mehdi Ahmed M AM Zhou Chenhao C Turrell Gavin G Walpole Euan E Porceddu Sandro S Frazer Ian H IH Chandra Janin J

Cancer gene therapy 20221227 4

Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Ca ...[more]

PMID: 36575316

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Project description:BackgroundHead and Neck Cancer (HNC) is a major cause of cancer morbidity and mortality in the United States, but the burden is not evenly distributed. Rural and racial disparities are obvious across the HNC continuum. Most HNC disparities research have emphasized individual factors perpetuating rural and racial disparities, ignoring the role of community-level factors.MethodsWe analyzed data from the Surveillance Epidemiology and End Results (SEER) program's "Specialized HNC-Human Papillomavirus (HPV) Census-Tract SES" datafile (2010-2016). In addition to cancer patient characteristics, this data includes a socioeconomic status (SES) quintile based on the patient's census-tract. Our outcome variables included whether the HNC patient 1) was diagnosed at a distant stage, 2) received initial treatment two or more months after diagnosis, 3) received radiation therapy, 4) survived two years after diagnosis. We tested for differences across SES quintiles, in the full sample and then within rural/racial categories. We then tested for differences between each rural/racial category conditional on SES quintile.ResultsFor both HPV(-) and HPV + HNCs, patients in higher SES census-tracts have 8-10% lower rates of distant stage diagnoses and delayed treatment initiation, and 12.0-14.5% higher survival rates than patients in lower SES census-tracts. Radiation treatment only varied across SES quintiles in HPV + HNC patients. We find little evidence of rural-urban differences within each socioeconomic quintile. However, within lower SES quintiles, we found significant racial disparities in delayed detection and treatment. These differences were largest in the lowest SES quintile, as non-Hispanic Black patients reported 10-11% higher rates of delayed detection and treatment initiation than non-Hispanic White patients.ConclusionsOur research illustrates the value and constraints in leveraging community-level factors in health disparities research that can ultimately assist in designing effective policies that address and achieve rural and racial cancer equity.

Project description:ObjectiveWe investigated the correlations between cyclin-dependent kinase 4/6 (CDK4/6) levels and human papillomavirus (HPV) infection state in head and neck squamous cell cancer (HNSCC). The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC.MethodsMultiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas (TCGA), and the mRNA levels and copy number variations (CNVs) of CDK4 and CDK6 were strictly analyzed. Overall survival (OS) curves were produced using the Kaplan-Meier method, and survival differences between groups were assessed by the log-rank test. Next, gene set enrichment analysis (GSEA) was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC. Last, lymphoid cell infiltrates in each type of HNSCC were explored, and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource (TIMER) analysis.ResultsOverexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV- HNSCC (CDK6: top 40%vs. bottom 40%, P=0.885; CDK4: top 40% vs. bottom 40%, P=0.267). In HPV+ HNSCC, CDK6 but not CDK4 was a relevant factor for OS (CDK6: top 40% vs. bottom 40%, P=0.002; CDK4: top 40% vs. bottom 40%, P=0.452). GSEA found that overexpressed CDK6 in HPV+ HNSCC inhibited pathways involved in the tumor immune response, suggesting its roles in antitumor immunity. TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+ HNSCC, which led to tumor response suppression.ConclusionsCDK6, but not CDK4, is a poor prognostic marker specific in HPV+ HNSCC patients. Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity. Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.

Dataset Information

HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

Publications

HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

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