title: Frequent microsatellite instability in sporadic tumors of the upper urinary tract.
abstract: Urothelial carcinoma of the renal pelvis and ureter may develop sporadically or as a manifestation of hereditary nonpolyposis colorectal cancer. The majority of hereditary nonpolyposis colorectal cancer is caused by mutation of the human DNA mismatch repair (MMR) genes and is detected by associated microsatellite instability (MSI). Seventy-three unselected urothelial carcinomas of the ureter and/or renal pelvis were screened for MSI using the National Cancer Institute-designated reference panel (plus BAT40). Instability of at least two microsatellite markers (MSI-high) was detected in 15 samples (21%). Immunohistochemical staining of the MMR proteins (hMSH2, hMLH1, or hMSH6) was absent in 13 of 15 (87%) MSI tumors, and alteration of coding sequence microsatellites (TGFbetaRII, Bax, hMSH3, and hMSH6) was found at frequencies of 7-33% in these samples. Tumors with MSI had significantly different clinical and histopathological features including higher prevalence in female patients, low tumor stage and grade, and a papillary and frequently inverted growth pattern. Our results suggest a molecular pathway of tumorigenesis that is similar to MMR-deficient colorectal cancers and consistent with the notion that the site distributions of hereditary or sporadic MSI-high tumors may reflect tissue-specific susceptibility to lesions processed by the MMR machinery.
authors.affiliation: Institute of Pathology, University of Regensburg, 93042 Regensburg, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Livia
authors.initials: L
authors.lastname: Zanardo
authors.forename: Tina
authors.initials: T
authors.lastname: Bocker-Edmonston
authors.forename: Hagen
authors.initials: H
authors.lastname: Blaszyk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.forename: Kerstin
authors.initials: K
authors.lastname: Junker
authors.forename: Wolf
authors.initials: W
authors.lastname: Wieland
authors.forename: Ruth
authors.initials: R
authors.lastname: Knuechel
authors.forename: Josef
authors.initials: J
authors.lastname: Rueschoff
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007682:Kidney Pelvis / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014516:Ureteral Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein