Development of a Prognostic Signature Based on Autophagy-related Genes for Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor with relative low survival rate. Increasingly evidences have emphasized the importance of autophagy in cancer initiation, progression, and the responses to cancer treatment. This study aimed to investigate the potential biological and prognostic significance of autophagy-related genes (ARGs) in HNSCC patients. We collected a list of ARGs from Human Autophagy Database and obtained expression profiles and clinical information of HNSCC samples from the Cancer Genome Atlas (TCGA) portal. Differential expression analysis and functional enrichment analysis were performed by R software. The prognostic value of differentially expressed ARGs was detected by Cox regression analysis and prognosis-related ARGs were subjected to LASSO regression analysis. Univariate and multivariate Cox regression analysis were applied to identify promising independent prognosticators for HNSCC. A total of 35 differentially expressed ARGs were screened out and functional enrichment analysis results indicated these genes were mainly associated with autophagy-related biological processes and pathways. Seven prognosis-related ARGs (ITGA3, CDKN2A, FADD, NKX2-3, BAK1, CXCR4, and HSPB8) were selected to construct a risk signature, which proved to be effective in predicting the survival rate of HNSCC patients. Moreover, univariate analysis showed risk score, tumor stage, T stage, and N stage were negatively correlated with patient overall survival and the multivariate Cox regression analysis results indicated risk score, age, and N stage was significantly associated with patient prognosis. Our findings may provide novel evidences for the diagnosis and prognosis evaluation for HNSCC.

Jin Y ，Qin X 《-》

Prognostic Correlation of an Autophagy-Related Gene Signature in Patients with Head and Neck Squamous Cell Carcinoma.

Considerable evidence indicates that autophagy plays a vital role in the biological processes of various cancers. The aim of this study is to evaluate the prognostic value of autophagy-related genes in patients with head and neck squamous cell carcinoma (HNSCC). Transcriptome expression profiles and clinical data acquired from The Cancer Genome Atlas (TCGA) database were analyzed by Cox proportional hazards model and Kaplan-Meier survival analysis to screen autophagy-related prognostic genes that were significantly correlated with HNSCC patients' overall survival. Functional enrichment analyses were performed to explore biological functions of differentially expressed autophagy-related genes (ARGs) identified in HNSCC patients. Six ARGs (EGFR, HSPB8, PRKN, CDKN2A, FADD, and ITGA3) identified with significantly prognostic values for HNSCC were used to construct a risk signature that could stratify patients into the high-risk and low-risk groups. This signature demonstrated great value in predicting prognosis for HNSCC patients and was indicated as an independent prognostic factor in terms of clinicopathological characteristics (sex, age, clinical stage, histological grade, anatomic subdivision, alcohol history, smoking status, HPV status, and mutational status of the samples). The prognostic signature was also validated by data from the Gene Expression Omnibus (GEO) database and International Cancer Genome Consortium (ICGC). In conclusion, this study provides a novel autophagy-related gene signature for predicting prognosis of HNSCC patients and gives molecular insights of autophagy in HNSCC.

Yang C ，Mei H ，Peng L ，Jiang F ，Xie B ，Li J ... -  《-》

Development and Validation of an Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma.

HNSCC is the sixth most frequent type of malignant carcinoma with a low prognosis rate. In addition, autophagy is important in cancer development and progression. The purpose of this study is to investigate the potential significance of ARGs in the diagnosis and treatment of HNSCC. Expression data and clinical information of HNSCC samples were collected from the TCGA database, and a list of ARGs was obtained from the MSigDB. Then, we used R software to perform differential expression analysis and functional enrichment analysis. Further analysis was also performed to find out the survival-related ARGs in HNSCC, and two prognosis-related ARGs, FADD and NKX2-3, were selected to construct a prognosis prediction model. Moreover, some methods were applied to validate the prognosis prediction model. Finally, we used cell lines and clinical tissue samples of HNSCC to analyze the importance of FADD and NKX2-3. We screened a total of 38 differentially expressed ARGs, and enrichment analysis showed that these genes were mainly involved in autophagy. Then, we selected FADD and NKX2-3 to construct a prognosis model and the risk score calculated by the model was proved to be effective in predicting the survival of HNSCC patients. Additionally, significant differences of the clinicopathological parameters could also be observed in the risk scores and the expression of NKX2-3 and FADD. The expression of FADD and NKX2-3 in cell lines and HNSCC tissue samples also showed the same trends. ARGs may be a potential biomarker for HNSCC prognosis, and targeted therapies for FADD and NKX2-3 are possible to be a new strategy of HNSCC treatment.

Liu C ，Wu W ，Xu M ，Mi J ，Xu L ，Wang R ... -  《-》

Development and validation of a novel survival model for head and neck squamous cell carcinoma based on autophagy-related genes.

In view of the critical role of autophagy-related genes (ARGs) in the pathogenesis of various diseases including cancer, this study aims to identify and evaluate the potential value of ARGs in head and neck squamous cell carcinoma (HNSCC). RNA sequencing and clinical data in The Cancer Genome Atlas (TCGA) were analyzed by univariate Cox regression analysis and Lasso Cox regression analysis model established a novel 13- autophagy related prognostic genes, which were used to build a prognostic risk model. A multivariate Cox proportional regression model and the survival analysis were used to evaluate the prognostic risk model. Moreover, the efficiency of prognostic risk model was tested by receiver operating characteristic (ROC) curve analysis based on data from TCGA database and Gene Expression Omnibus (GEO). Besides, the other independent datasets from Human Protein Atlas dataset (HPA) also applied. 13 ARGs (GABARAPL1, ITGA3, USP10, ST13, MAPK9, PRKN, FADD, IKBKB, ITPR1, TP73, MAP2K7, CDKN2A, and EEF2K) with prognostic value were identified in HNSCC patients. Subsequently, a prognostic risk model was established based on 13 ARGs, and significantly stratified HNSCC patients into high- and low-risk groups in terms of overall survival (OS) (HR = 0.379，95% CI: 0.289-0.495, p < 0.0001). The multivariate Cox analysis revealed that this model was an independent prognostic factor (HR = 1.506, 95% CI = 1.330-1.706, P < 0.001). The areas under the ROC curves (AUC) were significant for both the TCGA and GEO, with AUC of 0.685 and 0.928 respectively. Functional annotation revealed that model significantly enriched in many critical pathways correlated with tumorigenesis, including the p53 pathway, IL2 STAT5 signaling, TGF beta signaling, PI3K Ak mTOR signaling by gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). In addition, we developed a nomogram shown some clinical net could be used as a reference for clinical decision-making. Collectively, we developed and validated a novel robust 13-gene signatures for HNSCC prognosis prediction. The 13 ARGs could serve as an independent and reliable prognostic biomarkers and therapeutic targets for the HNSCC patients.

Ren Z ，Zhang L ，Ding W ，Luo Y ，Shi Z ，Shrestha B ，Kan X ，Zhang Z ，Ding J ，He H ，Hu X ... -  《-》

Identification of an autophagy-related prognostic signature in head and neck squamous cell carcinoma.

Autophagy-related genes (ARGs) have been significantly implicated in tumorigenesis and served as promising prognostic biomarkers for human cancer. Hence, this study was aimed to develop an ARGs-based prognostic signature for Head and neck squamous cell carcinoma (HNSCC). Prognostic ARG candidates were identified by univariate and multivariate Cox regression analysis in the training dataset (TCGA-HNSC) and incorporated into a 3-ARGs (EGFR, FADD, and PARK2) prognostic signature which was further verified in two independent validation cohorts (GSE41613 and GSE42743). Kaplan-Meier plots, Cox regression analyses, and receiver operating characteristics curves (ROC) were employed to evaluate the prognostic prediction of 3-ARGs signature. Differential expression of these 3 ARG between cancer and normal counterparts as well as their associations with autophagy markers were assessed in 60 pairs of freshly collected HNSCC and adjacent non-tumor samples and datasets from Human Protein Atlas, respectively. Patients with high-risk score had significantly inferior overall survival. Multivariate regression analyses revealed that 3-ARGs signature could be an independent prognostic factor after adjusting various clinicopathological parameters. ROC analyses revealed high predictive accuracy and sensitivity of the 3-ARGs signature. Increased mRNA and protein expression of EGFR, FADD, and PARK2 were found in HNSCC samples, and their expression significantly correlated with the abundances of ATG5, Beclin1, and LC3. Our results reveal that 3-ARGs signature is a powerful prognostic biomarker for HNSCC, which could be integrated into the current prognostic regime to realize individualized outcome prediction. EGFR, FADD, and PARK2 likely contributed to autophagy during HNSCC tumorigenesis.

Jiang Y ，Li Y ，Ge H ，Wu Y ，Zhang Y ，Guo S ，Zhang P ，Cheng J ，Wang Y ... -  《-》