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HPV induction of APOBEC3 enzymes mediate overall survival and response to cisplatin in head and neck cancer.

ABSTRACT: Human papillomavirus (HPV) is associated with the development of head and neck squamous cell carcinomas (HNSC). Cisplatin is used to treat HNSC and induces DNA adducts including interstrand crosslinks (ICLs). Previous reports have shown that HPV positive HNSC patients respond better to cisplatin therapy. Our previous reports highlight that loss of base excision repair (BER) and mismatch repair (MMR) results in cisplatin resistance. Of importance, uracil DNA glycosylase (UNG) is required to initiate the BER response to cisplatin treatment and maintain drug sensitivity. These previous results highlight that specific cytidine deaminases could play an important role in the cisplatin response by activating the BER pathway to mediate drug sensitivity. The APOBEC3 (A3) family of cytidine deaminases are enzymes that restrict HPV as part of the immune defense to viral infection. In this study, the Cancer Genome Atlas (TCGA) HNSC data were used to assess the association between the expression of the seven proteins in the A3 cytidine deaminase family, HPV-status and survival outcomes. Higher A3 G expression in HPV-positive tumors corresponds with better overall survival (OS) (HR 0.33, 95 % CI 0.11-0.93, p = 0.04). FaDu and Scc-25 HNSC cell lines were used to assess alterations in A3, BER and MMR expression in response to cisplatin. We demonstrate that A3, Pol?, and MSH6 knockdown in HNSC cells results in resistance to cisplatin and carboplatin as well as an increase in the rate of ICL removal in FaDu and Scc-25 HNSC cells. Our results suggest that A3s activate BER in HNSC, mediate repair of cisplatin ICLs and thereby, sensitize cells to cisplatin which likely contributes to the improved patient responses observed in HPV infected patients.

SUBMITTER: Conner KL

PROVIDER: S-EPMC7033022 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Project description:ImportanceData are limited on the prognostic value of human papillomavirus (HPV) status for head and neck carcinoma subsites.ObjectiveTo determine whether HPV positivity at each head and neck subsite is associated with improved overall survival.Design, setting, and participantsThis retrospective population-based cohort study used the National Cancer Database to identify patients diagnosed with head and neck squamous cell carcinomas from January 1, 2010, to December 31, 2014. Patients were classified according to the location of their primary malignancy into 1 of the 6 main subsites of the upper aerodigestive tract: oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, and sinonasal tract. Patients were also classified by their HPV status. Data collection for this study took place from January 1, 2010, to December 31, 2014. Data analysis was conducted from August 1, 2017, to September 30, 2017.Main outcomes and measuresThe difference in 5-year overall survival between patients with HPV-positive status and those with HPV-negative status in various head and neck carcinoma subsites; the role of HPV status in an unadjusted Cox multivariate regression model.ResultsOf the 175 223 total number of patients identified (129 634 [74.0%] male; 45 589 [26.0%] female; mean [SD] age, 63.1 [11.9] years), 133 273 (76.1%) were ineligible and 41 950 (23.9%) were included in the sample. This sample included 16 644 patients (39.7%) with HPV-positive tumors and 25 306 (60.3%) with HPV-negative tumors. Patients with an HPV-positive status were more likely to be younger, be white, be male, present with local T category tumors, and have poor differentiation on histologic examination. HPV-positive status was associated with survival at 4 tumor subsites: oral cavity (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87), oropharynx (HR, 0.44; 95% CI, 0.41-0.47), hypopharynx (HR, 0.59; 95% CI, 0.45-0.77), and larynx (HR, 0.71; 95% CI, 0.59-0.85). The HPV status was the greatest factor in survival outcome between the HPV-positive and -negative cohorts at the oropharynx subsite (77.6% vs 50.7%; survival difference, 26.9%; 95% CI, 25.6%-28.2%) and hypopharynx subsites (52.2% vs 28.8%; survival difference, 23.4%; 95% CI, 17.5%-29.3%). For the nasopharynx (HR, 1.03; 95% CI, 0.75-1.42) and sinonasal tract (HR, 0.63; 95% CI, 0.39-1.01) subsites, HPV-positive status was not an independent prognostic factor.Conclusions and relevanceHuman papillomavirus positivity was associated with improved survival in 4 subsites (oropharynx, hypopharynx, oral cavity, and larynx), and the largest survival difference was noted in the oropharynx and hypopharynx subsites. In the nasopharynx and sinonasal tract subsites, HPV positivity had no association with overall survival. Given these results, routine testing for HPV at the oropharynx, hypopharynx, oral cavity, and larynx subsites may be warranted.

Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common malignancy that emanates from the lips, mouth, paranasal sinuses, oropharynx, larynx, nasopharynx, and from other pharyngeal cancers. The availability of high-throughput expression data has made it possible to use global gene expression data to analyze the relationship between metabolic-related gene expression and clinical outcomes in HNSCC patients.MethodIn this study, we used RNA sequencing (RNA-seq) data from the cancer genome atlas (TCGA), with validation in the GEO dataset to profile the metabolic microenvironment and define potential biomarkers for metabolic therapy.ResultsWe extracted data for 529 patients and 327 metabolic genes (198 upregulated and 129 downregulated genes) in the TCGA database. Carbonic anhydrase 9 (CA9) and CA6 had the largest logFCs in the upregulated and downregulated genes, respectively. Our Cox regression model data showed 51 prognostic-related genes with lysocardiolipin acyltransferase 1 (LCLAT1) and choline dehydrogenase (CHDH) being associated with the highest risk (HR = 1.144, 95% CI = 1.044 ~ 1.251) and the lowest risk (HR = 0.580, 95% CI = 0.400 ~ 0.839) in HNSCC, respectively. We next used the ROC curve to evaluate whether the differentially expressed metabolic-related genes could serve as early predictors of HNSCC. The findings showed an AUC of 0.745 and 0.618 in the TCGA and GEO analysis, respectively. Besides, the ability for the genes to predict clinicopathological HNSCC status was analyzed and the data showed that the AUC for age, gender, grade, stage, T, M, and N was 0.520, 0.495, 0.568, 0.606, 0.577, 0.476, and 0.673, respectively, in the TCGA dataset. On the other hand, the AUC for age, gender, stage, T, M, N, smoking, and HPV16-pos was 0.599, 0.531, 0.622, 0.606, 0.616, 0.550, 0.614, 0.519, and 0.397, respectively, in the GEO dataset.ConclusionTaken together, our study unearths a novel metabolic gene signature for the prediction of HNSCC prognosis based on the TCGA dataset. Our signature might point out the metabolic microenvironment disorders and provides potential treatment targets and prognostic biomarkers.

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HPV induction of APOBEC3 enzymes mediate overall survival and response to cisplatin in head and neck cancer.

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