Analysis of p53, p16MTS1, p21WAF1 and H-ras in archived bladder tumours from workers exposed to aromatic amines

Abstract

Summary Exposure to aromatic amines is considered a major risk factor for the development of bladder cancer. In this study, we have analysed the pattern of point mutations in several tumour genes in 21 cases of bladder cancer arising among western European workers exposed to aromatic amines in an attempt to determine whether this exposure may be associated with a unique spectrum of mutations. Of the four genes analysed (p53, p16mTs1, p21WAF1 and H-ras), only p53 showed a high frequency of mutations (in 8 out of 21 cases, 38%). Two mutations were found in p16, one in H-ras and none in p21 exon 3. All mutations were at G:C base pairs, mostly at non-CpG residues. This spectrum of mutations, which is highly suggestive of an involvement of exogenous carcinogens, is however identical to the spectrum of p53 mutations detected in bladder cancers of the general population. In exposed workers, p53 mutations were associated with tumour grade and with high occupational and tobacco exposure. Taken together, our data suggest that the same carcinogens may be responsible for the development of bladder cancers in workers exposed to aromatic amines and in the general population.

TP53 mutations in workers exposed to occupational carcinogens

“…Yasunaga and coworkers [Yasunaga et al, 1997] described a peculiar TP53 mutation spectrum in bladder tumors from exposed workers with predominantly C to T transitions and a hot spot at codons 151-152, features not found in tumors from people not exposed to aromatic amines. However, in other studies the type (majority G:C to A:T) or distribution of TP53 mutations in occupational bladder cancers has not differed from other bladder cancers suggesting that the etiology is common in both groups or that TP53 mutation is a late event and not related to etiology [Esteve et al, 1995;Taylor et al, 1996;Sorlie et al, 1998]. Increased odds ratios for p53 nuclear over-expression were found by Zhang and coworkers [Zhang et al, 1994] in bladder cancers from workers in dye-and cooking-associated occupations, but the association with cigarette smoking was much stronger.…”

“…These carcinogens pose an increased risk to bladder cancer in the dye/ink industry [Sorlie et al, 1998]. Another important known risk factor for bladder cancer is smoking.…”

Histone deacetylase inhibitor trichostatin A inhibits the growth of bladder cancer cells through induction of p21WAF1 and G1 cell cycle arrest

“…Loss of p21 WAF1 expression has been reported as a significant and independent predictor of bladder cancer progression 4,5 . Functional loss of p21 WAF1 through genetic changes such as mutation is rare in bladder cancer 6,7 . Thus it is postulated that epigenetic events such as DNA methylation and histone deacetylation may account for p21 WAF1 loss in bladder cancer.…”

Increased oxidative stress with gene alteration in urinary bladder urothelium after the Chernobyl accident

“…Alteration of the p53 tumor-suppressor gene is an important indicator of late progression events, with a close relationship to genetic instability (Yamamoto et al, 1997). The majority of studies have demonstrated involvement of ras oncogenes in human bladder carcinogenesis as an early event (Sorlie et al, 1998). It has been indicated that inflammatory mediators, such as numerous cytokines and growth factors, can activate H-ras, an important component in their growth-promoting signaling pathways (Shibayama et al, 1999).…”