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Alterations
of the p53 Gene in Occupational Bladder Cancer in Workers Exposed to Aromatic
Amines |
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Yutaka Yasunaga,
Hirofumi Nakanishi, Norifumi Naka, Tsuneharu Miki, Takahiro Tsujimura, Hiroaki
Itatani, Akihiko Okuyama, and Katsuyuki Aozas |
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Departments
of Pathology (YY, HN, NN, KA) and Urology (TM, AO), Osaka University Medical
School, Suita; and Departments of Pathology (TT) and Urology (HI), Sumitomo
Hospital, Osaka, Japan |
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Epidemiologic studies have
revealed an increased risk for development of transitional cell carcinoma
(TCC) among dye workers/painters occupationally exposed to aromatic amines
such as benzidine, [beta]-naphthylamine, orthotoluidine, and aniline. In
the present study, p53 gene mutations in 26 patients with bladder lesions
occupationally exposed to aromatic amines were examined by single-strand
conformation polymorphism analysis of PCR-amplified DNA segments, followed
by direct sequencing. All were male, and age at admission ranged from 43
to 75 (median 66) years. Twenty-nine biopsy specimens were from primary
lesions; 17 (61%) of these lesions were from TCC including one carcinoma
in situ (CIS); 11 were from dysplasia; and 1 was taken from normal-looking
transitional epithelium adjoining TCC. TCC lesions included 12 with low-grade
(Grade 1 or 2) and 5 with high-grade (Grade 3 or CIS) changes. Twenty-four
recurrent lesions were biopsied in 16 patients: TCC was found in 12 lesions
(50%), CIS in 1 (4%), and dysplasia in 11 (46%). All lesions were localized
within the submucosa except for two, which invaded into the muscle layers.
PCR-single-strand conformation polymorphism analysis demonstrated that mutations
(a) occurred in both dysplasia and in normal-looking epithelium, in addition
to TCC lesions; (b) were at different sites in the p53 gene in concurrent
or metachronous lesions; and (c) occurred in exon 5 in approximately 70%
of lesions, especially at codons 151 and 152. C to T transitions were predominantly
seen. These findings clearly show differences in the pattern of p53 mutation
in occupational versus nonoccupational bladder lesions. Because both common
and unique point mutations were found in p53 in concurrent and metachronous
lesions, our results suggest that the multifocality of occupational bladder
cancer arises both from multiple clonal lesions (field change) and from
the dissemination of a single clone. |
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