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Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation

ABSTRACT: Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSC). Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. Here, we assessed the transcriptional profiles of 10 paired primary and subsequent recurrent HPV-related oropharyngeal squamous cell carcinomas (OPSCCs) using an exome-capture hybrid RNA sequencing assay. Principal componenent analysis using the expression data from the top 500 most variable genes revealed that 29.3% of the variance was aassociated with tumor status (i.e., primary vs recurrent tumor). Four of the primary/recurrent tumor pairs demonstrated greater clustering based on the patient of origin rather than the tumor status (primary vs recurrent). Additionally, two of the recurrences were distant, two were local, and the remaining six were regional. The recurrent tumors did not cluster necessairly based on site of recurrence. Unsupervised heirarchical clustering of the top 500 most variable genes revealed a correlation between recurrent tumors and metabolic gene expression while the primary tumors demonstrated increased expression in several immunologic related genes, mitogenic signaling, and epigenetic signaling genes. Using the PANTHER GO-Slim biological process pathway analysis, we identified enrichment of processes involved in biosynthesis, metabolism including oxidative phosphorylation, and Wnt signaling. Using gene set enrichment analysis, we observed enrichment in oxidative phosphorylation, fatty acid metabolism, and glutathione metabolism as well as MYC, P53-dependent DNA damage repair, and NRF2 pathway gene expression among the recurrent HPV-associated OPSCCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165883 | GEO | 2021/02/02

REPOSITORIES: GEO

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Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-active OPCs and normal benign uvula/tonsil tissues and determine what biological processes and pathways are affected in HPV-active tumors. ANALYSIS 5: Two-condition, one-color experiment: HPV-active oropharyngeal tumor samples and normal benign uvula/tonsil tissues. Biological replicates: 12 HPV active samples and 4 Normal samples.

Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-negative and HPV-inactive OPCs from both African American and European American patients, and determine their biological and racial differences. ANALYSIS 4: Four-condition, one-color experiment: African American (AA) HPV-inactive, African American (AA) HPV-negative, European American (EA) HPV-inactive, European American (EA) HPV-negative oropharyngeal tumor samples. Biological replicates: 4 AA HPV Inactive samples, 8 AA HPV Negative samples, 4 EA HPV Inactive samples and 8 EA HPV Negative samples,

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Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation

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