p53 mutations in phenacetin-associated human urothelial carcinomas

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 promutagenk 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 hi 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.

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…This was suggested to reflect a response to air pollution toxicity. TP53 mutations in PA-associated urothelial carcinomas (Petersen et al, 1993) have been reported, but show variability. Microsatellite instability was found in about 40% of RE sinonasal carcinomas (Uryu et al, 2005).…”

Carcinomas of the renal pelvis associated with smoking and phenacetin abuse:p53 mutations and polymorphism of carcinogen-metabolising enzymes

“…In a previous study, 3 of the 8 p53 mutations detected in phenacetin-associated urothelial carcinomas were G:C=A:T transitions at CpG sites (Petersen et al, 1993). This mutation type is considered to result from spontaneous deamination of 5-methylcytosine and is more likely to be a consequence of chronic tissue damage than of promutagenic DNA lesions by metabolites of phenacetin.…”

Clonality and Genetic Divergence in Multifocal Low-Grade Superficial Urothelial Carcinoma as Determined by Chromosome 9 and p53 Deletion Analysis

“…However, most of the molecular genetic studies (eg, Goto et al, 1997;Habuchi et al, 1993;Petersen et al, 1993;Spruck et al, 1994;Xu et al, 1996) have focused mainly on invasive and high-grade cancers. The determination of identical genetic alterations in later stages of tumor development could reflect monoclonal occurrence of multiple tumors as well as dominant overgrowth of the most malignant tumor cell clone, the latter mimicking monoclonality.…”