ALDH2, CCNE1 and SMAD3 are Potential Prognostic Markers for Upper Tract Urothelial Carcinoma Revealed by Massively Parallel Sequencing.
Purpose: upper tract urothelial carcinoma (UTUC) is the predominant subtype of the renal pelvis carcinoma but current knowledge about the molecular properties and prognostic markers is sparse. In this study, we examined the genome-wide mRNA expression spectrum of UTUC aiming to characterize the molecular basis of this cancer, and identify potential prognostic markers and thus facilitate the clinical practices. Experimental Design: we compared the whole mRNA expression spectrum of cancer and matched normal tissues in 10 patients with UTUC using massively parallel sequencing, thereafter the protein levels and prognostic roles of ALDH2, CCNE1 and SMAD3 were evaluated under an independent validation set comprising of 104 patients. Results: mRNA down-regulation of ALDH2 and up-regulation of SMAD3 and CCNE1 in UTUC were revealed by expression profiling. And low protein expression of ALDH2 was associated with an adverse outcome for patients (p < 0.0001). Whereas high CCNE1 and SMAD3 were associated with adverse clinical outcome (p < 0.0001). And multivariate analysis revealed that all these three molecular markers were independent prognostic predictors. Besides, compared to the pathological TNM classification, All ALDH2, CCNE1 and SMAD3 were more competent in identifying patient subgroup with high mortality risk, and the molecular markers were able to predict the survival difference in the patients of T2 and T3 subgroup (p < 0.001), which could not be achieved by TNM staging. Conclusions: This is the ?rst prospective study that characterizes genome-wide mRNA expression profile of UTUC. We revealed the prognostic significance of ALDH2, CCNE1 and SMAD3, and these molecular marker were more robust than TNM system in clinical outcome prediction. Overall design: Whole mRNA expression spectrum of cancer and matched normal tissues in 10 patients with UTUC was obtained by using massively parallel sequencing