title: Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract.
abstract: A subset of upper urinary tract urothelial cell carcinomas (UUC), arising sporadically or as a manifestation of hereditary non-polyposis colorectal cancer, displays microsatellite instability (MSI). MSI tumours are characterized by defective mismatch repair and accumulation of frameshift mutations in numerous genes harbouring repeats in their coding sequences. We have evaluated the incidence of MSI in UUC and the intratumoral distribution of mutations in 13 candidate target genes. A total of 58 unselected UUC were screened for MSI using the panel of five mononucleotide markers recently recommended by the National Cancer Institute for a precise MSI assessment. Four tumours displayed MSI (7%), among which at least three had alterations in the genes MSH3, BAX, MRE11, RAD50. Mutations in genes involved in key cellular pathways (ATR, DNA-PKcs, MBD4, TCF-4, MSH6, and BLM) were further detected. BAX and MRE11 mutations tend to present homogeneously within the three MSI UUC. Immunohistochemistry (MLH1, MSH2, MSH6) showed that loss of mismatch repair protein expression occurred in all MSI UUC defining the gene defect and that MRE11 and RAD50 mutations were associated with their concomitant loss expression. In conclusion, MSI UUC represent a small proportion of UUC in which BAX and MRE11 mutations are frequent and may play a role early in UUC tumorigenesis.
authors.affiliation: Department of Urology, University Paris VII, Saint-Louis Hospital, Paris, France. pierre.mongiat-artus@sls.aphp.fr
authors.forename: P
authors.initials: P
authors.lastname: Mongiat-Artus
authors.forename: C
authors.initials: C
authors.lastname: Miquel
authors.forename: M
authors.initials: M
authors.lastname: Van der Aa
authors.forename: O
authors.initials: O
authors.lastname: Buhard
authors.forename: R
authors.initials: R
authors.lastname: Hamelin
authors.forename: H
authors.initials: H
authors.lastname: Soliman
authors.forename: C
authors.initials: C
authors.lastname: Bangma
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.forename: P
authors.initials: P
authors.lastname: Teillac
authors.forename: T
authors.initials: T
authors.lastname: van der Kwast
authors.forename: F
authors.initials: F
authors.lastname: Praz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology*