Integrative Analysis of miRNAs Identifies Clinically Relevant Epithelial and Stromal Subtypes of Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: The objective of this study is to characterize the role of miRNAs in the classification of head and neck squamous cell carcinoma (HNSCC).Experimental Design: Here, we analyzed 562 HNSCC samples, 88 from a novel cohort and 474 from The Cancer Genome Atlas, using miRNA microarray and miRNA sequencing, respectively. Using an integrative correlations method followed by miRNA expression-based hierarchical clustering, we validated miRNA clusters across cohorts. Evaluation of clusters by logistic regression and gene ontology approaches revealed subtype-based clinical and biological characteristics.Results: We identified two independently validated and statistically significant (P < 0.01) tumor subtypes and named them "epithelial" and "stromal" based on associations with functional target gene ontology relating to differing stages of epithelial cell differentiation. miRNA-based subtypes were correlated with indi-vidual gene expression targets based on miRNA seed sequences, as well as with miRNA families and clusters including the miR-17 and miR-200 families. These correlated genes defined pathways relevant to normal squamous cell function and pathophysiology. miRNA clusters statistically associated with differential mutation patterns including higher proportions of TP53 mutations in the stromal class and higher NSD1 and HRAS mutation frequencies in the epithelial class. miRNA classes correlated with previously reported gene expression subtypes, clinical characteristics, and clinical outcomes in a multivariate Cox proportional hazards model with stromal patients demonstrating worse prognoses (HR, 1.5646; P ¼ 0.006).Conclusions: We report a reproducible classification of HNSCC based on miRNA that associates with known pathologically altered pathways and mutations of squamous tumors and is clinically relevant.

Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

“…All miR-200 members have been shown to play an important part in repressing malignant cell transformation and in inhibiting tumor initiation, and have thus been characterized as tumor suppressors [ 127 , 128 ]. More specifically, the miR-200 family has been reported to negatively modulate the progress of EMT in various cancers, including HNSCC [ 129 ], by controlling the expression of transcriptional repressors ZEB1 and ZEB2, the so-called EMT master regulators [ 126 , 130 , 131 ].…”

A Super-Enhancer Driven by FOSL1 Controls miR-21-5p Expression in Head and Neck Squamous Cell Carcinoma

“…Although a significant progress on the pathogenesis of HNSCC has been made in the past decades, the exact molecular mechanisms are still not well understood. Increasing evidences implicates that dysregulation of miRNAs has a critical role in the development and progression of HNSCC (4)(5)(6)(7)(8)(9)(10).…”

Identification of miR-203a, mir-10a, and miR-194 as predictors for risk of lymphovascular invasion in head and neck cancers

“…One of the predicted targets of miR-203a in our analysis was Semaphorin 5a that is associated with lymph node metastasis and adverse prognosis [ 58 ]. Integrative Analysis of miRNAs in HNSCC has previously identified miR-194 to be associated with the epithelial sub-type of HNSCC [ 59 ]. However, to the best of our knowledge no study has shown the role of miR-203, miR-194 and miR-10a as a prognostic indicator of LVI in HNSCC.…”