Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies with complex phenotypic, etiological, biological, and clinical heterogeneities. Previous studies have proposed different clinically relevant subtypes of HNSCC, but little is known about its corresponding prognosis or suitable treatment strategy. Here, we identified 101 core genes from three prognostic pathways, including mTORC1 signaling, unfold protein response, and UV response UP, in 124 pairs of tumor and matched normal tissues of HNSCC. Moreover, we identified three robust subtypes associated with distinct molecular characteristics and clinical outcomes using consensus clustering based on the gene expression profiles of 944 HNSCC patients from four independent datasets. We then integrated the genomic information of The Cancer Genome Atlas (TCGA) HNSCC cohort to comprehensively evaluate the molecular features of different subtypes and screen for potentially effective therapeutic agents. Cluster 1 had more arrested oncogenic signaling, the highest immune cell infiltration, the highest immunotherapy and chemotherapeutic responsiveness, and the best prognosis. By contrast, Cluster 3 showed more activated oncogenic signaling, the lowest immune cell infiltration, the lowest immunotherapy and chemotherapy responsiveness, and the worst prognosis. Our findings corroborate the molecular diversity of HNSCC tumors and provide a novel classification strategy that may guide for prognosis and treatment allocation.
Highlights
MATERIALS AND METHODSHead and neck squamous cell carcinoma (HNSCC) is a primary malignant tumor that develops from the mucosal epithelium in the pharynx, larynx, and oral cavity, causing 600,000 new cases worldwide each year (Cancer Genome Atlas Network, 2015; Alsahafi et al, 2019; Canning et al, 2019)
To screen for robust oncogenic signaling across different HNSCC cohorts, we applied GSVA based on the expression profile and identified several differentially activated pathways between paired tumor and normal samples in The Cancer Genome Atlas (TCGA) (n = 44), GSE107591 (n = 23), and GSE127165 (n = 57) datasets (Figure 1A and Supplementary Figure 1A)
Univariate Cox regression of overall survival (OS) based on GSVA scores in TCGA HNSCC cohort identified three candidate prognostic pathways with statistical significance, including mTORC1 signaling (HR = 0.65, 95% CI = 0.49–0.84, p < 0.01), unfolded protein response (UPR) pathway (HR = 0.73, 95% CI = 0.57–0.93, p < 0.01), and UV response UP (HR = 0.75, 95% CI = 0.57–0.98, p = 0.03) (Figure 1B)
Summary
MATERIALS AND METHODSHead and neck squamous cell carcinoma (HNSCC) is a primary malignant tumor that develops from the mucosal epithelium in the pharynx, larynx, and oral cavity, causing 600,000 new cases worldwide each year (Cancer Genome Atlas Network, 2015; Alsahafi et al, 2019; Canning et al, 2019). Recent large-scale transcriptomic profiling has uncovered the molecular landscape of HNSCC, where genes involved in receptor tyrosine kinase (RTK)/RAS/PI3K signaling, cell cycle, cell death, and immunity signaling pathways are found frequently altered (Cancer Genome Atlas Network, 2015). These studies, on the one hand, underscored the complexity and heterogeneity of HNSCC tumors and, on the other hand, alerted that the prognosis and treatment strategy may be highly variable among tumors of different molecular features (Cancer Genome Atlas Network, 2015). There is an urgent need to develop validated biomarkers to stratify HNSCC patients with potentially different survival outcome and treatment responsiveness and to reduce undesirable side effects
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