TY - JOUR
T1 - Integrative analysis of miRNAs identifies clinically relevant epithelial and stromal subtypes of head and neck squamous cell carcinoma
AU - Holt, Jeremiah
AU - Walter, Vonn
AU - Yin, Xiaoying
AU - Marron, David
AU - Wilkerson, Matthew D.
AU - Choi, Hyo Young
AU - Zhao, Xiaobei
AU - Jo, Heejoon
AU - Hayes, David Neil
AU - Ko, Yoon Ho
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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 individual 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.
AB - 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 individual 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.
UR - http://www.scopus.com/inward/record.url?scp=85100415578&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-0557
DO - 10.1158/1078-0432.CCR-20-0557
M3 - Article
C2 - 33148669
AN - SCOPUS:85100415578
SN - 1078-0432
VL - 27
SP - 831
EP - 842
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -