title: Global gene expression profiling identifies ALDH2, CCNE1 and SMAD3 as potential prognostic markers in upper tract urothelial carcinoma.
abstract: BACKGROUND
  Current knowledge about the molecular properties and prognostic markers of upper tract urothelial carcinoma (UTUC) is sparse and often based on bladder urothelial carcinoma (UC), which is thought to share common risk factors with UTUC. However, studies have suggested that differences exist regarding tumor behavior and molecular biology of these cancers, comprehensive investigations are needed to guide the clinical management of UTUC. In recent years, massively parallel sequencing has allowed insights into the biology of many cancers, and molecular prognostic markers based on this approach are rapidly emerging. The goal of this study was to characterize the gene expression patterns of UTUC using massively parallel sequencing, and identify potential molecular markers for prognosis in patients with UTUC.
  
  
  METHODS
  We compared the genome-wide mRNA expression profile of cancer and matched normal tissues from 10 patients with UTUC to identify significantly deregulated genes. We also examined the protein levels of prognostic marker candidates in 103 patients with UTUC, and tested the association of these markers with overall survival using Kaplan-Meier model and Cox regression.
  
  
  RESULTS
  Functional enrichment of significantly deregulated genes revealed that expression patterns of UTUC were characterized by disorders of cell proliferation and metabolism. And we also compared the expression profile of UTUC with that of bladder UC. Our results highlighted both shared (e.g. disorders of cell cycling and growth signal transduction) and tumor-specific (e.g. abnormal metabolism in UTUC and disruptions of adhesion pathways in bladder UC) features of these two cancers. Importantly, we identified that low protein expression of ALDH2 while high CCNE1 and SMAD3 were significantly associated with increased depth (*P <0.05) and lower overall survival (***P <0.0001) in an independent set of 103 patients. Multivariate Cox regression revealed that all these three genes were independent prognostic indicators in patients with UTUC (***P <0.001).
  
  
  CONCLUSIONS
  In conclusion, our study characterized the comprehensive expression profile of UTUC and highlighted both commons and differences in expression patterns between UTUC and bladder UC. And we, for the first time, revealed that ALDH2, CCNE1 and SMAD3 are associated with prognosis in patients with UTUC.
authors.affiliation: Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. doctor_wusong@126.com.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Jiahao
authors.initials: J
authors.lastname: Chen
authors.forename: Pei
authors.initials: P
authors.lastname: Dong
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Zhang
authors.forename: Yingying
authors.initials: Y
authors.lastname: He
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Jialou
authors.initials: J
authors.lastname: Zhu
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Cheng
authors.forename: Xianxin
authors.initials: X
authors.lastname: Li
authors.forename: Aifa
authors.initials: A
authors.lastname: Tang
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Yaoting
authors.initials: Y
authors.lastname: Gui
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.forename: Guosheng
authors.initials: G
authors.lastname: Yang
authors.forename: Fangjian
authors.initials: F
authors.lastname: Zhou
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Cai
authors.forename: Rongfu
authors.initials: R
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000401:mortality; D007682:Kidney Pelvis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D015203:Reproducibility of Results; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics; D014571:Urologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*
chemical_list: D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D051900:Smad3 Protein; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial