Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract

Christian Hafner, Ruth Knuechel, Livia Zanardo, Wolfgang Dietmaier, Hagen Blaszyk, John Cheville, Ferdinand Hofstaedter, Arndt Hartmann

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

Multifocality and recurrence of urothelial carcinoma may result from either the field effect of carcinogens leading to oligoclonal tumors or monoclonal tumor spread. Previous molecular studies, favoring the monoclonality hypothesis, are mostly limited to the urinary bladder. We investigated genetic alterations in a total of 94 synchronous or metachronous multifocal tumors from 19 patients with at least one tumor both in the upper and lower urinary tract. Loss of heterozygosity (LOH) was determined using eight markers on chromosome 9 and one marker on 17p13 (p53). Microsatellite instability was investigated at six loci and protein expression of MSH2 and MLH1 was evaluated by immunohistochemistry. In addition, exons 5-9 of the p53 gene were sequenced. Deletions at chromosome 9 were found in 73% of tumors and at 17p13 in 18% of tumors. There was no significant difference in the frequency of LOH in the upper and lower urinary tract. Deletions at 9p21 were significantly correlated with invasive tumor growth. The pattern of deletion revealed monoclonality of all tumors in nine patients. In five patients there were at least two tumor clones with different genetic alterations. In four of these patients the different clones occured in the bladder and subsequently in the ureter and renal pelvis. All four patients with p53 mutations revealed identical mutations in all tumors. Thus, multifocal urothelial carcinomas are frequently monoclonal, whereas others show oligoclonality, providing molecular evidence for field cancerization. Intraluminal tumor cell seeding appears to be an important mechanism of multifocal occurence and recurrence of urothelial carcinomas.

Original languageEnglish (US)
Pages (from-to)4910-4915
Number of pages6
JournalOncogene
Volume20
Issue number35
DOIs
StatePublished - Aug 9 2001

Keywords

  • LOH
  • Oligoclonality
  • P53 mutation
  • Upper and lower urinary tract
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Hafner, C., Knuechel, R., Zanardo, L., Dietmaier, W., Blaszyk, H., Cheville, J., Hofstaedter, F., & Hartmann, A. (2001). Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. Oncogene, 20(35), 4910-4915. https://doi.org/10.1038/sj.onc.1204671