NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer

Schrank, Travis P.; Prince, Andrew C.; Sathe, Tejas; Wang, Xiaowei; Liu, Xinyi; Alzhanov, Damir; Burtness, Barbara; Baldwin, Albert S.; Yarbrough, Wendell G.; Issaeva, Natalia

doi:10.18632/oncotarget.28232

Cited by 8 publications

(7 citation statements)

References 74 publications

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“…Tumors assigned to the high expression vs. low expression subtypes were also distinguished by differences in somatic gene alterations, mutational signatures, HPV gene expression, HPV genome integration, and genomic methylation profiles [ 65 ]. The gene profile that identified the two subtypes of HPV+ HNSCC was based on high or low NF-κB signaling and fully recapitulated previous subtypes that our group defined based on the presence or absence of inactivating defects in TRAF3 or CYLD or associated gene expression changes [ 64 , 65 , 73 ]. Based on high vs. low expression of genes in the NF-κB signature, roughly 50% of patients were assigned to each subtype and previously reported molecular markers of good or poor prognosis appropriately sorted with the two subtypes; specifically, estrogen receptor-alpha expression [ 74 , 75 ] segregated with the subtype having high NF-κB activity and good survival, and PIK3CA defects segregated with the subtype having low NF-κB activity and poor survival.…”

Section: Hpv Carcinogenesis and Prognostic Biomarkers To Guide Therapysupporting

confidence: 68%

“…The association of HPV integration with outcome in head and neck tumors has had varied and conflicting results, with some studies showing no correlation with survival [ 54 , 62 ], some a positive correlation with viral integration [ 56 , 63 ], and others an unfavorable correlation [ 55 , 64 ]. Interestingly, to our knowledge, all studies using transcriptional (e.g., RNAseq) methods to ascertain integration status have found integration to be associated with poor prognosis [ 55 , 64 , 65 ]. A recent multiomics study of uterine cervical cancer categorized integration sites as productive or silent based on the presence or absence of viral-human fusion transcripts [ 66 ].…”

Section: Hpv Carcinogenesis and Prognostic Biomarkers To Guide Therapymentioning

confidence: 99%

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De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy

Yarbrough,

Schrank,

Burtness

et al. 2024

Viruses

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Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

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Section: Hpv Carcinogenesis and Prognostic Biomarkers To Guide Therapysupporting

confidence: 68%

Section: Hpv Carcinogenesis and Prognostic Biomarkers To Guide Therapymentioning

confidence: 99%

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy

Yarbrough,

Schrank,

Burtness

et al. 2024

Viruses

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“…The impact of NF-kB on regulating the inflammatory process has been extensively studied, but its role in the carcinogenic process, particularly in HPV+ tumors, still requires further efforts [ 74 ]. However, it has already been demonstrated that modulating this pathway impacts the clinical outcome of HPV+ head and neck cancer patients [ 75 ]. Additionally, Cai et al demonstrated that NF-kB is critical in tumor progression in HPV+ cervical cancer mediated by PD-L1 [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

E7 Oncogene HPV58 Variants Detected in Northeast Brazil: Genetic and Functional Analysis

et al. 2023

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Cervical cancer is associated with persistent infections by high-risk Human Papillomavirus (HPV) types that may have nucleotide polymorphisms and, consequently, different oncogenic potentials. Therefore, this study aimed to evaluate the genetic variability and structural effects of the E7 oncogene of HPV58 in cervical scraping samples from Brazilian women. The study was developed with patients from hospitals in the metropolitan area of Recife, PE, Brazil. The most frequent HPV types were, in descending order of abundance, HPV16, 31, and 58. Phylogenetic analysis demonstrated that the isolates were classified into sublineages A2, C1, and D2. Two positively selected mutations were found in E7: 63G and 64T. The mutations G41R, G63D, and T64A in the E7 protein reduced the stability of the protein structure. Utilizing an NF-kB reporter assay, we observed a decrease in the NK-kB pathway activity with the HPV58-E7 variant 54S compared to the WT E7. The other detected E7 HPV58 variants presented similar NF-kB pathway activity compared to the WT E7. In this study, it was possible to identify mutations that may interfere with the molecular interaction between the viral oncoproteins and host proteins.

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“…The proinflammatory NFκB is variably activated in HPV(+) versus HPV(−) HNSCC, which may be due to differences between canonical and noncanonical forms ( 10 ). HPV proteins inhibit NFκB; however, the noncanonical pathway is overexpressed in HPV(+) tumors, with higher activity associated with longer survival ( 11 ). In oral cancers more generally, NFκB has been described as having both protumor and antitumor activity, serving as a potential target for the treatment of HNSCC ( 11, 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…HPV proteins inhibit NFκB; however, the noncanonical pathway is overexpressed in HPV(+) tumors, with higher activity associated with longer survival ( 11 ). In oral cancers more generally, NFκB has been described as having both protumor and antitumor activity, serving as a potential target for the treatment of HNSCC ( 11, 12 ). Activator protein-1 (AP-1) TFs, including JunB, are master regulators of epithelial differentiation, and also differ by HPV status, with higher expression in HPV(−) tumors ( 13 ), reflecting the fact that HPV(+) HNSCCs are generally less differentiated than HPV(−) ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes

Qin,

Li,

Henry

et al. 2023

Cancer Research Communications

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DNA methylation is a vital early step in carcinogenesis. Most findings of aberrant DNA methylation in head and neck squamous cell carcinomas (HNSCC) are array-based with limited coverage and resolution, and mainly explored by human papillomavirus (HPV) status, ignoring the high heterogeneity of this disease. In this study, we performed whole-genome bisulfite sequencing (WGBS) on a well-studied HNSCC cohort (n=36) and investigated the methylation changes between fine-scaled HNSCC subtypes in relation to genomic instability, repetitive elements, gene expression, and key carcinogenic pathways. The previously observed hypermethylation phenotype in HPV-positive (HPV+) tumors compared to HPV-negative tumors was robustly present in the immune-strong (IMU) HPV+ subtype but absent in the highly keratinized (KRT) HPV+ subtype. Methylation levels of IMU tumors were significantly higher in repetitive elements, and methylation showed a significant correlation with genomic stability, consistent with the IMU subtype having more genomic stability and better prognosis. Expression quantitative trait methylation (cis-eQTM) analysis revealed extensive functionally-relevant differences, and differential methylation pathway analysis recapitulated gene expression pathway differences between subtypes. Consistent with their characteristics, KRT and HPV-negative tumors had high regulatory potential for multiple regulators of keratinocyte differentiation, which positively correlated with an expression-based keratinization score. Together, our findings revealed distinct mechanisms of carcinogenesis between subtypes in HPV-positive HNSCC and uncovered previously ignored epigenomic differences and clinical implications, illustrating the importance of fine-scale subtype analysis in cancer.

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NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer

Cited by 8 publications

References 74 publications

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy

E7 Oncogene HPV58 Variants Detected in Northeast Brazil: Genetic and Functional Analysis

Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes

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