High P4HA1 expression is an independent prognostic factor for poor overall survival and recurrent-free survival in head and neck squamous cell carcinoma.

BACKGROUND: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) plays a critical role in modulating the extracellular matrix and promoting tumor progression in various cancers. However, the association between P4HA1 and head and neck squamous cell carcinomas (HNSCC) has not been thoroughly elucidated to date. METHODS: P4HA1 mRNA and protein expression in cancer and normal tissues were analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, and Human Protein Atlas databases. Quantitative PCR was applied to determine P4HA1 mRNA expression levels in 162 paired HNSCC and adjacent normal tissues. The cBioPortal for Cancer Genomics was utilized to explore P4HA1 genetic alterations in HNSCC. Then, KEGG analysis of P4HA1 co-expressed genes in HNSCC was conducted using ClueGo in Cytoscape. RESULTS: P4HA1 mRNA and protein levels were significantly increased in HNSCC tissues compared with normal tissues. High P4HA1 expression in HNSCC tissues was significantly associated with tumor category, lymphatic metastasis and pathological stage. The area under summary receiver operating characteristic curve of TCGA and validation cohort was 0.887 and 0.883, respectively. Moreover, elevated P4HA1 expression was associated with unfavorable OS (HR: 1.728, P = .001) and RFS (HR: 2.025, P = .002) in HNSCC patients. CONCLUSIONS: This integrated analysis provides strong evidence that increasing P4HA1 expression is significantly associated with the carcinogenesis of HNSCC. Additionally, high P4HA1 expression serves as both diagnostic biomarker and independent prognostic factor for poor OS and RFS in HNSCC patients.

The clinical significance of HOXA9 promoter hypermethylation in head and neck squamous cell carcinoma.

BACKGROUND: The purpose of the current study was to assess the association between HOXA9 (homeobox A9) promoter methylation and head and neck squamous cell carcinoma (HNSCC) and its diagnostic value. METHODS: Quantitative methylation-specific PCR (qMSP) was applied to measure HOXA9 promoter methylation levels in 145 paired HNSCC and corresponding normal tissue samples. Data from the Cancer Genome Atlas (TCGA) database (n = 578; 528 HNSCC and 50 normal) were also analyzed. RESULTS: Significantly higher levels of HOXA9 promoter methylation were detected in HNSCC, compared with normal, tissues (our cohort: P = 1.06E-35; TCGA cohort: P = 3.06E-39). Moreover, HOXA9 methylation was significantly increased in patients with advanced tumor (T) stage, lymph node metastasis, and advanced clinical stage. Areas under the receiver characteristic curves (AUCs) based on our cohort and TCGA data were 0.930 and 0.967, respectively. CONCLUSION: In summary, our study reveals that HOXA9 promoter hypermethylation contributes to the risk of HNSCC and its progression and metastasis. Additionally, HOXA9 hypermethylation is a potential biomarker for the early diagnosis and screening of patients with HNSCC.

The Association and Clinical Significance of CDKN2A Promoter Methylation in Head and Neck Squamous Cell Carcinoma: a Meta-Analysis.

BACKGROUND/AIMS: The association between cyclin-dependent kinase inhibitor 2A (CDKN2A) hypermethylation and head and neck squamous cell carcinoma (HNSCC) risk has been investigated by a number of studies. However, these studies have not demonstrated consistent results. Moreover, the role of CDKN2A methylation in HNSCC carcinogenesis and its clinical significance remain unclear. METHODS: We performed a systematic meta-analysis based on 72 articles (including 3399 HNSCCs, 668 premalignant lesions, and 2393 normal controls) from the PubMed, Google Scholar, Web of Science, Embase, China National Knowledge Infrastructure and Wanfang databases. RESULTS: Our study showed a significant increase in the frequency of CDKN2A methylation during HNSCC carcinogenesis (HNSCC vs. normal controls, odds ratio (OR) = 6.72, P < 0.01; HNSCC vs. precancerous lesions, OR = 1.89, P < 0.05; precancerous lesions vs. normal controls, OR = 14.70, P < 0.01). Moreover, CDKN2A methylation was significantly associated with gender (OR = 1.34; P < 0.05) and lymph node metastasis (OR = 2.32; P < 0.01). The area under summary receiver operating characteristic curve (AUC) for diagnosis of HNSCC based on all samples and saliva sample subgroup were 0.77 and 0.96, respectively. Additionally, CDKN2A hypermethylation was significantly associated with shorter overall survival (OS) (hazard ratio (HR) = 1.01, P < 0.05) and recurrence-free survival (RFS) (HR = 1.77, P < 0.05). CONCLUSION: Our findings indicate CDKN2A methylation is involved in the carcinogenesis, progression, and metastasis of HNSCC. Furthermore, methylated CDKN2A could be a potential diagnostic and prognostic biomarker for HNSCC.

Construction of a Ferroptosis-Related Gene Signature for Head and Neck Squamous Cell Carcinoma Prognosis Prediction.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant cancers, and few studies have demonstrated the value of ferroptosis-related genes in prognosis. METHODS: The original counts of RNA sequencing data and clinicopathological data were obtained from TCGA and GSE65858 datasets. Common ferroptosis-related genes related to prognosis were identified from the training set and were included in LASSO to determine the best prognosis. To evaluate the efficacy, time-dependent ROC and Kaplan-Meier (KM) survival analyses were applied. Moreover, univariate and multivariate Cox regression analyses were used to screen independent parameters of prognosis and build a nomogram. Eventually, possible biological pathways were proposed based on GSEA. RESULTS: Among 242 ferroptosis-related genes, we identified that the FLT3, IL6, Keap1, NQO1, SOCS1 and TRIB3 genes were significantly connected with HNSCC patient prognosis as a six-gene signature. After, the patients were divided into high- and low-risk groups based on the six-gene signature. The KM survival curves demonstrated that the high-risk group had worse OS (p < 0.0001) and higher AUC values (0.654, 0.735, and 0.679 for 1-, 3-, and 5-year survival, respectively) for the prognostic signature of the six genes compared with other genes, which were also validated in the GSE65858 dataset. Moreover, GSEA suggested that the epithelial mesenchymal transition pathway was abundant and that the mesenchymal status in the high-risk group was substantially higher than that in the low-risk group. Finally, the immune microenvironment and differences in the content of immune cell types were demonstrated. CONCLUSION: We established a six-ferroptosis-related-gene model crossing clinical prognostic parameters that can predict HNSCC patient prognosis and provide a reliable prognostic evaluation tool to assist clinical treatment decisions.

Promoter hypermethylation of CD133/PROM1 is an independent poor prognosis factor for head and neck squamous cell carcinoma.

PROM1 has played a pivotal role in the identification and isolation of tumor stem cells. This study aimed to assess the association between PROM1 promoter methylation and head and neck squamous cell carcinoma (HNSCC), and its diagnostic and prognostic value.Bioinformatic analysis was performed using data from the Cancer Genome Atlas-HNSC and Gene Expression Omnibus datasets.The results showed that PROM1 promoter was hypermethylated in HNSCCs compared with normal head and neck tissues (P = 4.58E-37). The area under the receiver-operating characteristic curve based on methylated PROM1 data was 0.799. In addition, PROM1 hypermethylation independently predicted poor overall survival (hazard ratio [HR]: 1.459, 95% confidence interval [CI]: 1.071-1.987, P = .016) and recurrence-free survival (HR: 1.729, 95% CI: 1.088-2.749, P = .021) in HNSCC patients. Moreover, PROM1 methylation was weakly negatively correlated with its mRNA expression (Pearson r = -0.148, P < .001).In summary, our study reveals that methylated PROM1 might serve as a valuable diagnostic biomarker and predictor of poor survival for HNSCC patients. PROM1 hypermethylation might partially contribute to its downregulation in HNSCC.

Diagnostic potential of methylated DAPK in brushing samples of nasopharyngeal carcinoma.

BACKGROUND: The death-associated protein kinase (DAPK) gene is an important member of the apoptotic pathway and is inactivated by abnormal methylation in numerous cancers, including nasopharyngeal carcinoma (NPC). However, the diagnostic value of DAPK methylation in brushing samples and tissue samples of NPC remains unclear. METHODS: We conducted a systematic meta-analysis based on 17 studies (including 386 tissue cases, 233 brushing cases, and 296 blood cases). RESULTS: Our results revealed an association between methylated DAPK and increased risk of NPC in blood, brushing, and tissue samples. In addition, the comparison of the pooled sensitivity, specificity, and area under the curve of methylated DAPK in brushing and tissue samples demonstrated the non-inferior effectiveness of methylated DAPK in brushing samples to monitor the development of NPC.