Abstract 4007: Integrative analysis of miRNAs classify two distinct stages of epithelial cell differentiation in head and neck squamous cell carcinoma (HNSCC)

Abstract

Abstract Background Analyses of microRNA expression profiles have revealed that many microRNAs are expressed aberrantly and correlate with tumorigenesis, progression, and prognosis of various solid tumors. However, several miRNA analyses of head and neck squamous cell carcinoma (HNSCC) have been inconsistent among studies due to the small sample size. Method 366 HNSCC samples from two independent subsets of patients from UNC and The Cancer Genome Atlas (TCGA) were analyzed by the different platforms, microRNA microarray and miRNA Seq, respectively. Using the integrative correlations method, 41 miRNAs were selected as highly reliable across the different platforms. Tumor statistically significant subtypes were identified using consensus clustering and miRNA SigClust test statistic. miRNA clusters were validated across independent cohorts using centroids. Clinical and pathway associations of the subtypes were evaluated using logistic regression and gene ontology approaches. Results We identified two clinically relevant and genetically different subclasses of HNSCC that each related to a different stage of epithelial cell differentiation and were independently validated (P < 0.001). These were named epithelial and stromal subtypes according to their respective correlations with functional target gene ontology. Each subclass demonstrated significant differences in terms of mRNA signature (P < 0.001), primary tumor sites (P < 0.001), and a model of normal epithelial development. Multivariate analysis revealed that stromal subtype was independently associated with poor prognosis (hazard ratio of 1.677, P = 0.014.) We also found several microRNAs as strong regulators of subclass-specific gene expression networks in HNSCC. Among these miRNAs, the miR-200 family suppresses mesenchymal differentiation in HNSCC by downregulating expression of epithelial-mesenchymal transition. Conclusion Our findings assume that microRNAs are significant determinants of HNSCC subclass through their ability to regulate developmental growth and differentiation programs in epithelial cells. Taken together, our results delineate developmental microRNA expression signatures that both characterize and yield the phenotypic diversity of HNSCC subclasses, thus providing an expanded framework for understanding the pathogenesis of HNSCC. Note: This abstract was not presented at the meeting. Citation Format: Yoon Ho Ko, Vonn Walter, Michael Catalano, Xiaoying Yin, Patrick Kimes, Xiaobei Xiao Xiao, David Neil Hayes. Integrative analysis of miRNAs classify two distinct stages of epithelial cell differentiation in head and neck squamous cell carcinoma (HNSCC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4007. doi:10.1158/1538-7445.AM2015-4007