title: Microsatellite abnormalities and somatic down-regulation of mismatch repair characterize nodular-trabecular muscle-invasive urothelial carcinoma of the bladder.
abstract: OBJECTIVE
  To correlate histological infiltration patterns with genetic and mismatch repair (MMR) profiles in muscle-invasive bladder urothelial carcinomas (UroC).
  
  
  RESULTS
  Infiltration patterns were assessed in the deep compartment of muscle-invasive UroC (nodular-trabecular, 45 cases; infiltrative, 27 cases). Tumour compartment (superficial and deep to muscularis mucosa) analysis included: microsatellite pattern of TP53, RB1, WT1 and NF1 by polymerase chain reaction/denaturing gradient gel electrophoresis; mitotic, Ki67, in situ end labelling (ISEL) indices and DNA ploidy. MMR was assessed by MLH1 and MSH2 sequencing and immunohistochemistry in UroC with two or more abnormal microsatellite loci. Statistical differences were tested using anova and Fisher's exact tests. Infiltrative UroC showed lower Ki67 index 14.94 +/- 4.28, ISEL index 14.1 +/- 10.0 and shorter median survival (20 months) than nodular-trabecular UroC (Ki67 index 20.65 +/- 4.94, ISEL 20.2 +/- 22.7, 37-month survival, respectively). The genetic profile was significantly different for RB1 (P = 0.0003) and NF1 (P = 0.0023) only, being more frequently abnormal in nodular-trabecular UroC. A significant decrease in MLH1 or MSH2 protein expression with no gene mutations was identified in UroC with microsatellite abnormalities and a nodular-trabecular growth pattern.
  
  
  CONCLUSIONS
  Somatic down-regulation of MMR proteins in nodular-trabecular muscle-invasive UroC results in RB1/NF1 microsatellite abnormalities, correlating with higher cellular turnover and longer survival.
authors: Department of Pathology, University Hospital of Malaga, Malaga, Spain.
authors: J
authors: J
authors: Rubio
authors: A
authors: A
authors: Blanes
authors: J J
authors: JJ
authors: Sanchez-Carrillo
authors: S J
authors: SJ
authors: Diaz-Cano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D002467:Cell Nucleus / Q000473:pathology; D049109:Cell Proliferation; D053843:DNA Mismatch Repair; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009130:Muscle, Smooth / Q000473:pathology; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology; D025721:WT1 Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025721:WT1 Proteins; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins