Metabolism-associated molecular classification and prognosis signature of head and neck squamous cell carcinoma

Abstract

Although the fundamental processes and chemical changes in metabolic programs have been elucidated in many cancers, the expression patterns of metabolism-related genes in head and neck squamous cell carcinoma (HNSCC) remain unclear. The mRNA expression profiles from the Cancer Genome Atlas included 502 tumour and 44 normal samples were extracted. We explored the biological functions and prognosis roles of metabolism-associated genes in patients with HNSCC. The results indicated that patients with HNSCC could be divided into three molecular subtypes (C1, C2 and C3) based on 249 metabolism-related genes. There were markedly different clinical characteristics, prognosis outcomes, and biological functions among the three subtypes. Different molecular subtypes also have different tumour microenvironments and immune infiltration levels. The established prognosis model with 17 signature genes could predict the prognosis of patients with HNSCC and was validated using an independent cohort dataset. An individual risk scoring tool was developed using the risk score and clinical parameters; the risk score was an independent prognostic factor for patients with HNSCC. Different risk stratifications have different clinical characteristics, biological features, tumour microenvironments and immune infiltration levels. Our study could be used for clinical risk management and to help conduct precision medicine for patients with HNSCC.

Keywords: Head and neck squamous cell carcinoma; Immune infiltration; Metabolism; Prognosis model.

Fig. 1

Flow of study analyses and identification of HNSCC molecular subtypes using NMF consensus clustering. A: The flow chart of data analysis. B: NMF clustering using 249 metabolism-associated genes. Cophenetic correlation coefficient for K = 2–5 is shown. C: Consensus matrix of three HNSCC subclasses. D: PCA showed the distribution of three HNSCC subclasses. E: Individuals CA of three HNSCC subclasses. F: Kaplan-Meier curves of overall survival among three subclasses (C1, C2 and C3).

Fig. 2

Distributions of 249 metabolism-associated genes and key metabolic genes expressions among three HNSCC subclasses. A: Heatmap of correlation of metabolism-associated genes expression among three subclasses and different clinical features. B: Venn diagram showed the overlapped number of DEGs among three subtypes. C: Expression differences of several key metabolic genes among three subtypes (***: adjusted P values).

Fig. 3

Heatmap of significantly differential metabolism-associated pathways among three HNSCC subclasses.

Fig. 4

Comparisons of immune status among three subclasses. A: Heatmap showed the immune cells infiltration levels among three subclasses and different clinical features. B: Box plot comparing the immune cells scale of fraction among three subclasses (***: adjusted P values). C-E: Violin plot shown stromal, immune, and ESTIMATE scores among three subtypes (***: adjusted P values). F: Comparisons of expression levels of several immune checkpoint genes among three subtypes (***: adjusted P values).

Fig. 5

Identification of metabolism-associated genes prognosis model for HNSCC. A: Elastic net solution path of LASSO regression. B: Determination of the number of prognosis-related genes via the LASSO regression. C and D: Overall survival Kaplan-Meier curves of high-risk group and low-risk group for HNSCC patients in TCGA training group and validation group; E and F: Forest plots of univariate and multivariate cox regression analysis exhibited the association between risk score and overall survival in HNSCC patients.

Fig. 6

Association between risk score and three metabolism components. A: Comparisons of risk score among three subtypes (***: adjusted P values). B-D: Kaplan-Meier analysis curve of high- and low-risk groups in three subtypes.

Fig. 7

Evaluation of prognosis model and individual risk scoring system. A and B: ROC curves of prognostic signature in training dataset and validation dataset. C: ROC curves of risk score and other clinical parameters in HNSCC patients. D: Nomograph plot of predicted 1-,3-and 5-year overall survival probability based on metabolism-related genes signature. E: Heatmap showed prognosis signatures genes among clinical features.

Fig. 8

Comparisons of immune status between high- and low-risk groups. A-C: Violin plot comparing the stromal, immune, and ESTIMATE scores between high- and low-risk groups. D: Heatmap showed the immune cells distributions between high- and low-risk groups. E: Violin plot comparing the immune cells infiltration levels between high- and low-risk groups.

Fig. 9

Landscape of mutation profiles between high-and low-risk group in HNSCC patients. A and B: Waterfall plots of mutation information in each sample of high-and low-risk HNSCC patients; C and D: The variant classification and type, SNV class summary of in high-and low-risk groups of HNSCC patients; E and F: Gene cloud plots of mutations frequencies in high-and low-risk groups of HNSCC patients. G: Venn plot of overlapped mutation genes between high-risk and low-risk groups.

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