Influence of GSTM1, GSTT1, GSTP1 and NAT2 genotypes on the p53 mutational spectrum in bladder tumours.
Genetic polymorphisms affecting expression or activity of the corresponding enzymes can influence the risk of acquiring gene mutations and various cancers. We have studied 327 bladder cancer patients with regard to the functionally related polymorphisms of GSTM1, GSTT1, GSTP1 and NAT2 and analysed the p53 mutational status of their tumours. Fifty p53 mutations, 26% transversions and 74% transitions, were detected in 44 patients. P53 mutation frequency was significantly higher in higher-grade tumours than in low-grade tumours (OR = 2.09, 95% CI 1.44-3.02, adjusted for age and sex). Also, a significant association was found between tumour stage (Tis and T2+ vs. Ta and T1) and presence of the GSTP1 val allele (adjusted OR = 2.00, CI 1.14-3.52). Overall, there was no significant difference in frequency of p53 mutation among patients with different genotypes. Among patients with p53 mutation, transversions were significantly more frequent in GSTM1-negative as compared to GSTM1-positive individuals (OR = 5.18, CI 1.07-25.02, adjusted for age, sex and tumour stage). With one exception, all tumours with the most common type of transversion, G:C-C:G, occurred in GSTM1-negative patients. Among smokers, all transversions (3 of 3), but only 2 of 13 transitions, were found among carriers of the GSTP1 variant allele, and samples carrying at least 1 variant GSTP1 allele had more transitions at CpG sites than wild-type samples (adjusted OR = 4.61, CI 0.82-26.04). No significant associations were found for the NAT2 gene. Our results suggest that impaired glutathione conjugation may affect the mutation spectrum in critical target genes.
Ryk
Charlotta
C
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. charlotta.ryk@biosci.ki.se <charlotta.ryk@biosci.ki.se>
Berggren
Petra
P
Kumar
Rajiv
R
Hemminki
Kari
K
Larsson
Per
P
Steineck
Gunnar
G
Lambert
Bo
B
Hou
Sai-Mei
SM
D000217:Acyltransferases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D000217:Acyltransferases; D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; D016159:Tumor Suppressor Protein p53; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; C043403:fatty acyl ethyl ester synthase