Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract
- 9 August 2001
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 20 (35), 4910-4915
- https://doi.org/10.1038/sj.onc.1204671
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 occurred 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 occurrence and recurrence of urothelial carcinomasThis publication has 19 references indexed in Scilit:
- DISTINCT MICROSATELLITE ALTERATIONS IN UPPER URINARY TRACT TUMORS AND SUBSEQUENT BLADDER TUMORSJournal of Urology, 2001
- Multiple Mutation Analyses in Single Tumor Cells with Improved Whole Genome AmplificationThe American Journal of Pathology, 1999
- Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31Oncogene, 1999
- Clonal analysis of urothelial carcinomas in C3H/HeNBALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamineCarcinogenesis: Integrative Cancer Research, 1998
- Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis.JCI Insight, 1997
- Field cancerisation of the oral cavity: Comparison of the spectrum of molecular alterations in cases presenting with both dysplastic and malignant lesionsOral Oncology, 1997
- Field cancerisation and polyclonal p53 mutation in the upper aero- digestive tractOncogene, 1997
- Life‐time risk of different cancers in hereditary non‐polyposis colorectal cancer (hnpcc) syndromeInternational Journal of Cancer, 1995
- Metachronous multifocal development of urothelial cancers by intraluminal seedingThe Lancet, 1993
- Identification of p53 Gene Mutations in Bladder Cancers and Urine SamplesScience, 1991