Dataset Information

P63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma.

ABSTRACT: The complex heterogeneity of head and neck squamous cell carcinoma (HNSCC) reflects a diverse underlying etiology. This heterogeneity is also apparent within Human Papillomavirus-positive (HPV+) HNSCC subtypes, which have distinct gene expression profiles and patient outcomes. One aggressive HPV+ HNSCC subtype is characterized by elevated expression of genes involved in keratinization, a process regulated by the oncogenic transcription factor ΔNp63. Furthermore, the human TP63 gene locus is a frequent HPV integration site and HPV oncoproteins drive ΔNp63 expression, suggesting an unexplored functional link between ΔNp63 and HPV+ HNSCC. Here we show that HPV+ HNSCCs can be molecularly stratified according to ΔNp63 expression levels and derive a ΔNp63-associated gene signature profile for such tumors. We leveraged RNA-seq data from p63 knockdown cells and ChIP-seq data for p63 and histone marks from two ΔNp63^high HPV+ HNSCC cell lines to identify an epigenetically refined ΔNp63 cistrome. Our integrated analyses reveal crucial ΔNp63-bound super-enhancers likely to mediate HPV+ HNSCC subtype-specific gene expression that is anchored, in part, by the PI3K-mTOR pathway. These findings implicate ΔNp63 as a key regulator of essential oncogenic pathways in a subtype of HPV+ HNSCC that can be exploited as a biomarker for patient stratification and treatment choices.

SUBMITTER: Glathar AR

PROVIDER: S-EPMC9192977 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma.

Glathar Alexandra Ruth AR Oyelakin Akinsola A Gluck Christian C Bard Jonathan J Sinha Satrajit S

Frontiers in oncology 20220531

The complex heterogeneity of head and neck squamous cell carcinoma (HNSCC) reflects a diverse underlying etiology. This heterogeneity is also apparent within Human Papillomavirus-positive (HPV+) HNSCC subtypes, which have distinct gene expression profiles and patient outcomes. One aggressive HPV+ HNSCC subtype is characterized by elevated expression of genes involved in keratinization, a process regulated by the oncogenic transcription factor ΔNp63. Furthermore, the human <i>TP63</i> gene locus ...[more]

PMID: 35712470

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Project description:Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HR(E6/E7+) = 0.1, 95% confidence interval (CI) = 0.02-0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HR(DNA) = 0.9, 95% CI = 0.3-2.9; HR(p16) = 0.3, 95% CI = 0.1-1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HR(DNA+/E6/E7+) = 0.1, 95% CI = 0.02-1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HR(DNA+/E6-/E7-) = 3.4, 95% CI = 0.6-18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HR(p16+/E6/E7+) = 0.1, 95% CI = 0.02-0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HR(p16+/E6-/E7-) = 3.1, 95% CI = 1.2-7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when "HPV-associated" HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone.

Project description:The prognosis of patients with human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is poorer than those with HPV-positive HNSCC. The present study aimed to identify novel and specific biomarkers of HPV-negative HNSCC using bioinformatics analysis and associated experiments. The gene expression profiles of HPV-negative HNSCC tissues and corresponding clinical data were downloaded from The Cancer Genome Atlas database and used in a weighted gene co-expression network analysis. Genes in clinically significant co-expression modules were used to construct a protein-protein interaction (PPI) network. The genes demonstrating a high degree score in the PPI network and a high correlation with tumor grade were considered hub genes. The diagnostic value of the hub genes associated with HPV-negative and HPV-positive HNSCC was analyzed using differential expression gene (DEG) analysis, immunohistochemical (IHC) staining and a receiver operating characteristic (ROC) curve analysis. Seven genes [Serrate RNA effector molecule (SRRT), checkpoint kinase 2 (CHEK2), small nuclear ribonucleoprotein polypeptide E (SNRPE), proteasome 26S subunit ATPase 2 (PSMC2), origin recognition complex subunit 5 (ORC5), S100 calcium binding protein A7 and keratinocyte differentiation associated protein (KRTDAP)] were demonstrated to be hub genes in clinically significant co-expression modules. DEG, IHC and ROC curve analyses revealed that SRRT, CHEK2 and SNRPE were significantly upregulated in HPV-negative and HPV-positive HNSCC tissues compared with in adjacent tissues, and these genes demonstrated a high diagnostic value for distinguishing HNSCC tissues. However, PSMC2, ORC5 and KRTDAP were the only differentially expressed genes identified in HPV-negative HNSCC tissues, and these genes demonstrated a high diagnostic value for HPV-negative HNSCC. PSMC2, ORC5 and KRTDAP may therefore serve as novel and specific biomarkers for HPV-negative HNSCC, potentially improving the diagnosis and treatment of patients with HPV-negative HNSCC.

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

Dataset Information

P63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma.

Publications

p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma.

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