MicroRNA prognostic signature for nodal metastases and survival in esophageal adenocarcinoma.

Abstract

The incidence of esophageal adenocarcinoma is rapidly increasing and is now one of the leading causes of cancer death in the western world. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-encoding genes and are involved in the development, progression and prognosis of other malignancies. We hypothesized that global miRNA expression would predict survival and lymph node involvement in a cohort of surgically resected esophagus cancer patients. The miRNA analysis was performed using a custom Affymetrix microarray with probes for 462 known human, 2,102 predicted human, 357 mouse, and 238 rat miRNAs. Expression of miRNA was evaluated in 45 primary tumors, and the association of miRNA expression with patient survival and lymph node metastasis was assessed. The prognostic impact of identified unique miRNAs was verified with quantitative reverse transcriptase polymerase chain reaction. Our data indicate that the expression of individual human miRNA species is significantly associated with postresection patient survival. Using data from five unique miRNAs, we were further able to generate a combined miRNA expression signature that is associated with patient survival (p=0.005; hazard ratio 3.6) independent of node involvement and overall stage. The expression of three miRNAs (miR-99b and miR-199a_3p and _5p) was also associated with the presence of lymph node metastasis. These results suggest miRNA expression profiling could provide prognostic utility in staging esophagus cancer patients and treatment planning with endoscopic and neoadjuvant therapies. The alterations of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.