title: Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study.
abstract: BACKGROUND
  Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer.
  
  
  METHODS
  MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured.
  
  
  RESULTS
  MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability.
  
  
  CONCLUSIONS
  MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.
authors.forename: Anja
authors.initials: A
authors.lastname: Rogler
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoja
authors.forename: Johannes
authors.initials: J
authors.lastname: Giedl
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Sven
authors.initials: S
authors.lastname: Wach
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goebell
authors.forename: Bernd
authors.initials: B
authors.lastname: Wullich
authors.forename: Michael
authors.initials: M
authors.lastname: Stöckle
authors.forename: Jan
authors.initials: J
authors.lastname: Lehmann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Petsch
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Krankenhausstr, 8-10 91054 Erlangen, Germany. Robert.stoehr@uk-erlangen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C474762:MTUS1 protein, human; D025521:Tumor Suppressor Proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3