Identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma.

Jeff P Bruce,Ilan Weinreb,Benjamin Haibe-Kains,Ralph Gilbert,Bayardo Perez-Ordonez,Paul C Boutros,Angela B Y Hui,Shao Hui Huang,John Waldron,Fei-Fei Liu,Wei Shi,Wei Xu,Eric X Chen,Brian O’Sullivan,Daryl M Waggott

doi:10.18632/oncotarget.3005

Abstract

Despite significant improvement in locoregional control in the contemporary era of nasopharyngeal carcinoma (NPC) treatment, patients still suffer from a significant risk of distant metastasis (DM). Identifying those patients at risk of DM would aid in personalized treatment in the future. MicroRNAs (miRNAs) play many important roles in human cancers; hence, we proceeded to address the primary hypothesis that there is a miRNA expression signature capable of predicting DM for NPC patients. The expression of 734 miRNAs was measured in 125 (Training) and 121 (Validation) clinically annotated NPC diagnostic biopsy samples. A 4-miRNA expression signature associated with risk of developing DM was identified by fitting a penalized Cox Proportion Hazard regression model to the Training data set (HR 8.25; p < 0.001), and subsequently validated in an independent Validation set (HR 3.2; p = 0.01). Pathway enrichment analysis indicated that the targets of miRNAs associated with DM appear to be converging on cell-cycle pathways. This 4-miRNA signature adds to the prognostic value of the current "gold standard" of TNM staging. In-depth interrogation of these 4-miRNAs will provide important biological insights that could facilitate the discovery and development of novel molecularly targeted therapies to improve outcome for future NPC patients.

Highlights

Nasopharyngeal carcinoma (NPC) has a unique set of etiological, epidemiological and biological characteristics that renders it distinct from other epithelial malignancies of the head and neck region
TNM staging is the primary tool utilized clinically to prognosticate outcomes for nasopharyngeal carcinoma (NPC) patients. Other indicators such as tumor volume [2], plasma Epstein–Barr Viral (EBV) DNA titre [3, 4], and levels of expression of various proteins and transcripts [5,6,7] have been reported to correlate with clinical outcome; to date none has been universally adopted in the clinical management of NPC patients
Generation and validation of miRNA signature associated with risk of distant metastasis Using the Lasso method to fit a penalized Cox Proportional Hazards (PH) model to miRNA expression data from the Training cohort yielded 33 variables with non-zero coefficients (Table S1)

Summary

Methods and results

The expression of 734 miRNAs was measured in 125 (Training) and 121 (Validation) clinically annotated NPC diagnostic biopsy samples. A 4-miRNA expression signature associated with risk of developing DM was identified by fitting a penalized Cox Proportion Hazard regression model to the Training data set (HR 8.25; p < 0.001), and subsequently validated in an independent Validation set (HR 3.2; p = 0.01). Pathway enrichment analysis indicated that the targets of miRNAs associated with DM appear to be converging on cell-cycle pathways

Conclusions

INTRODUCTION

RESULTS

DISCUSSION

MATERIALS & METHODS