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p53 mutations in phenacetin-associated human urothelial carcinomas


Petersen, Iver; Ohgaki, Hiroko; Ludeke, Barbara I; Kleihues, Paul (1993). p53 mutations in phenacetin-associated human urothelial carcinomas. Carcinogenesis, 14(10):2119-2122.

Abstract

Chronic abuse of the analgesic drug phenacetin is associated with an increased risk of development of transitional cell carcinomas of the urinary tract. It is unclear whether phenacetin acts through chronic tissue damage (phenacetin nephropathy) or via a genotoxic metabolite causing promutagenic DNA lesions. In the present study, we investigated 15 urothelial carcinomas from 13 patients with evidence of phenacetin abuse. Tumors were screened for p53 mutations in exons 5-8 by single-strand conformation polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. p53 Mutations were detected in 8/14 primary tumors (57%). All except one were missense mutations located in exon 5 (three mutations), exon 6 (one), exon 7 (two) and exon 8 (one). The type of mutation varied, with a preference for CpG sites. A frameshift mutation resulting from the insertion of a single cytosine at codons 151/152 was detected in a bladder tumor and its lung metastasis. Urothelial carcinomas located in the renal pelvis and in the ureter of the same patient exhibited two different mutations, strongly suggesting that they developed independently. Another patient had tumors in the renal pelvis and bladder, both of which contained the same p53 mutation, indicating intracavitary metastatic spread. This demonstrates that screening of p53 mutations allows the clonal origin of tumors in patients with multiple primary and metastatic lesions to be determined. None of the tumors investigated contained mutations in codons 12, 13 or 61 of H-ras or K-ras protooncogenes

Abstract

Chronic abuse of the analgesic drug phenacetin is associated with an increased risk of development of transitional cell carcinomas of the urinary tract. It is unclear whether phenacetin acts through chronic tissue damage (phenacetin nephropathy) or via a genotoxic metabolite causing promutagenic DNA lesions. In the present study, we investigated 15 urothelial carcinomas from 13 patients with evidence of phenacetin abuse. Tumors were screened for p53 mutations in exons 5-8 by single-strand conformation polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. p53 Mutations were detected in 8/14 primary tumors (57%). All except one were missense mutations located in exon 5 (three mutations), exon 6 (one), exon 7 (two) and exon 8 (one). The type of mutation varied, with a preference for CpG sites. A frameshift mutation resulting from the insertion of a single cytosine at codons 151/152 was detected in a bladder tumor and its lung metastasis. Urothelial carcinomas located in the renal pelvis and in the ureter of the same patient exhibited two different mutations, strongly suggesting that they developed independently. Another patient had tumors in the renal pelvis and bladder, both of which contained the same p53 mutation, indicating intracavitary metastatic spread. This demonstrates that screening of p53 mutations allows the clonal origin of tumors in patients with multiple primary and metastatic lesions to be determined. None of the tumors investigated contained mutations in codons 12, 13 or 61 of H-ras or K-ras protooncogenes

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 January 1993
Deposited On:16 Oct 2018 13:10
Last Modified:24 Nov 2018 03:03
Publisher:Oxford University Press
ISSN:0143-3334
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/carcin/14.10.2119
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093carcin14102119 (Library Catalogue)

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