title: BUBR1 overexpression predicts disease-specific survival after nephroureterectomy in patients with upper tract urothelial carcinoma.
abstract: OBJECTIVE
  To date, there are few reliable markers to distinguish tumors with aggressive characteristics in upper tract urothelial carcinoma. The purpose of this study was to identify a biomarker related to genetic instability (chromosomal instability or microsatellite instability) with prognostic value, in patients with upper tract urothelial carcinoma.
  
  
  METHODS
  Expression of chromosomal instability-related markers (BUBR1, p53, polo-like kinase 1) and microsatellite instability-related markers (mismatch repair proteins, MLH1 and MSH2) were assessed by immunohistochemistry in 100 patients who had radical nephroureterectomy for upper tract urothelial carcinoma. Numerical aberrations of chromosomes 7, 9 and 17 were evaluated by fluorescence in situ hybridization, which allowed an estimation of the degree of chromosomal instability. BUB1B copy number was examined by array-based comparative genomic hybridization in 32 patients with upper tract urothelial carcinoma.
  
  
  RESULTS
  BUBR1 status was most significantly correlated with chromosomal instability-related and low mismatch repair parameters, according to the molecular biomarkers examined. Overexpression of BUBR1 is frequently detected in tumors with higher histological grade (P < 0.0001) and is significantly associated with chromosomal instability (P = 0.0071). Array-based comparative genomic hybridization revealed that no tumors (0%) showed BUB1B amplification and gain, indicating that overexpression of BUBR1 was independent of BUB1B copy number. For disease-specific survival, BUBR1 overexpression, lymphovascular invasion, pathological tumor stage, pathological lymph node involvement and low MSH2 expression were significant prognostic factors in univariate analyses. In multivariate analyses, BUBR1 overexpression was an independent prognostic factor for disease-specific survival (P = 0.0483, risk ratio 3.76, 95% confidence interval: 1.01-18.43).
  
  
  CONCLUSIONS
  BUBR1 may have significant potential as a biomarker for estimating disease-specific survival in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Oga
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Akao
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Taku
authors.initials: T
authors.lastname: Misumi
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Nakanori
authors.initials: N
authors.lastname: Fuji
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Keita
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kawai
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Ryo
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagao
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sakano
authors.affiliation: Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi hidde@yamaguchi-u.ac.jp.
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Matsuyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D043171:Chromosomal Instability; D055028:Comparative Genomic Hybridization; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015854:Up-Regulation; D014516:Ureteral Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000601:surgery*
chemical_list: D014408:Biomarkers, Tumor; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: BUBR1; chromosomal instability; disease-specific survival; microsatellite instability; upper tract urothelial carcinoma