5-hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144034 | GEO | 2020/09/01
REPOSITORIES: GEO
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Project description:BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied. RESULTS:We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(-) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(-) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(-) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(-) oral cavity cell lines. CONCLUSION:Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
| S-EPMC7672859 | biostudies-literature
Project description:ABSTRACT Two major subgroups of head and neck squamous cell carcinomas (HNSCC) are currently distinguished based on etiology and pattern of genetic alterations; tumors with biologically active human papillomavirus (HPV) and tumors without. It is at present unclear whether additional genetically distinct subgroups exist within HPV-negative HNSCC. Aim of this study is to genetically classify HNSCC without HPV involvement and to correlate the genetically defined classes to tumor and patient characteristics. By means of array comparative genomic hybridization (aCGH) we determined DNA copy number variation in thirty-nine HPV-negative, but further unselected HNSCC. Unsupervised analysis of aCGH data distinguished two genetic groups in HPV-negative HNSCC, one characterized by a low level of chromosomal alterations (N=9), and another by a high level of chromosomal alterations (N=30). Absence of chromosomal aberrations was significantly associated with wild-type TP53, a low level of alcohol consumption, a female gender and a better prognosis. The tumors were negative for microsatellite instability. The discovery of this new class of HNSCC with unique genetic and clinical characteristics has important consequences for future basic and clinical studies. All DNAs are isolated from fresh frozen HNSCC specimen. All tissue specimens were microdissected to obtain at least 90% tumor DNA. All sampels are hybridized against a pool of reference DNA of normal individuals of the opposite gender.
2009-03-11 | E-GEOD-11929 | biostudies-arrayexpress
Project description:ABSTRACT Two major subgroups of head and neck squamous cell carcinomas (HNSCC) are currently distinguished based on etiology and pattern of genetic alterations; tumors with biologically active human papillomavirus (HPV) and tumors without. It is at present unclear whether additional genetically distinct subgroups exist within HPV-negative HNSCC. Aim of this study is to genetically classify HNSCC without HPV involvement and to correlate the genetically defined classes to tumor and patient characteristics. By means of array comparative genomic hybridization (aCGH) we determined DNA copy number variation in thirty-nine HPV-negative, but further unselected HNSCC. Unsupervised analysis of aCGH data distinguished two genetic groups in HPV-negative HNSCC, one characterized by a low level of chromosomal alterations (N=9), and another by a high level of chromosomal alterations (N=30). Absence of chromosomal aberrations was significantly associated with wild-type TP53, a low level of alcohol consumption, a female gender and a better prognosis. The tumors were negative for microsatellite instability. The discovery of this new class of HNSCC with unique genetic and clinical characteristics has important consequences for future basic and clinical studies.
2009-03-12 | GSE11929 | GEO
Project description:5-hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers
| PRJNA602545 | ENA
Project description:Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV-associated HNSCC is increasing. The role of tumor microenvironment (TME) in viral infection and metastasis needs to be explored further. Thus we studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status using spatial transcriptomics.
2024-11-20 | GSE281978 | GEO
Project description:Gene expression analysis of p63 knockdown in 2 HPV+ HNSCC cell lines using RNA-seq, Genomic profiling of p63 binding across 2 HPV+ HNSCC cell lines, Epigenomic landscape of 2 HPV+ HNSCC cell lines
2022-04-19 | GSE182133 | GEO
Project description:Genome wide DNA methylation profiling of HPV positive and HPV negative head and neck squamous cell cancer (HNSCC) samples. The Illumina Infinium 450k Human DNA methylation Beadchip v1.1 was used to obtain DNA methylation profiles across approximately 485577 CpGs in 4 HPV positive and 4 HPV negative HNSCC tumors
2015-03-21 | GSE67114 | GEO
Project description:Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral CD45+ immune populations from HPV– and HPV+ HNSCC and healthy donors. A spectrum of transcriptional signatures in immune lineages ranging from similar to highly divergent was present in the tumor microenvironments (TME) in HPV– and HPV+ HNSCC. CD8+ and regulatory CD4+ T cells were similar in HPV– and HPV+ HNSCC, compared to significant differences between helper CD4+ T cells, B cells and myeloid cells. Further dissection of the major immune lineages identified unique cell states and differentiation trajectories. We contextualized our results by performing multispectral immunofluorescence and evaluating putative cell-cell communication based on spatial proximity, and found longer progression free survival in patients with enrichment of a CD4+ T follicular helper cell signature.
2019-11-13 | GSE139324 | GEO
Project description:The involvement of microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis, prognosis and response to therapy is becoming increasingly appreciated. The etiology of head and neck squamous cell carcinoma (HNSCC) is predominantly associated with the synergistic effects of tobacco and alcohol use, as well as Human Papilloma Virus (HPV) infection, which embodies a distinct clinical and biological phenotype. We sought to examine whether the profile of miRNAs in HNSCC varies based on HPV status, and to identify specific miRNAs altered in head and neck carcinogenesis. Total RNA was isolated from 16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines. The miRNA profile of 662 individual miRNAs in these tissues was examined by microarray. 18 miRNAs are significantly altered in their expression between normal tissues and HNSCC tumors and 5 miRNAs are identified as significantly differentially expressed between HPV-positive (HPV+) and HPV-negative (HPV-) tumors. A striking difference in expression pattern of miRNA was also observed between primary tissues and cell lines. These data suggest that the pattern of miRNA expression may be reflective of disease etiology, and may be useful in the realm of diagnostic biomarkers defining broadly responsive prevention and treatment strategies for HNSCC. These data also suggest that cultured tumor cell lines may be inappropriate for novel miRNA biomarker identification. Keywords: miRNA; Disease-state analysis Expression of 662 individual miRNA was assessed in16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines were arrayed
2010-05-19 | E-GEOD-11163 | biostudies-arrayexpress
Project description:Introduction: Human Papilloma Virus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC), between 15% and 35% of HNSCC harboring HPV, almost exclusively of subtype 16. Demographic and exposure differences between HPV-positive (+) and negative (-) HNSCCs suggest that HPV(+) tumors may constitute a subclass with different biology, while clinical differences have also been observed. In this study, gene expression profiles of HPV(+) and (-) tumors were compared to further explore the biological effect of HPV in HNSCC. Methods: Thirty-six HNSCC tumors were analyzed for gene expression using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV using consensus primers for HPV L1, E6 and E7 by PCR and RT-PCR. Results: Eight (22%) of 36 tumors were positive for HPV, all of the HPV 16 subtype, and the HPV positive samples also expressed viral HPV E6 mRNA determined by RT-PCR. Patients with HPV(+) HNSCCs were on average younger than those with HPV(-) tumors (mean age 50.2 vs. 58.7). Statistical analysis using Significance Analysis of Microarrays (SAM) based on HPV status as a supervising parameter resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a sub-set of these genes were verified by RT-PCR. Genes highly expressed in HPV(+) samples included cell cycle regulators (p16INK4A, p18 and CDK2) and transcription factors (TAF7L, RFC4, RPA2 and TFDP2). The microarray data were also investigated using DIGMap to map genes by chromosomal location. A large number of genes on chromosome 3q24-qter was found to be overrepresented in HPV(+) tumors. Conclusion: The gene expression profile associated with HPV reflects alterations in cell cycle and proliferation signals. Further investigation of differentially expressed genes may reveal the unique pathways in HPV(+) tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment. Keywords: HPV, HNSCC, head and neck cancer, human, human papilloma virus
2005-11-28 | GSE3292 | GEO