Association of GSTT1 non-null and NAT1 slow/rapid genotypes with von Hippel-Lindau tumour suppressor gene transversions in sporadic renal cell carcinoma

The von Hippel-Lindau (VHL) tumour suppressor gene is commonly mutated in r enal cell carcinoma of clear cell type (CCRCC). We investigated the possibl e relationship between VHL mutations in sporadic CCRCC and polymorphism of genes encoding enzymes involved in carcinogen metabolism: two cytochrome P4 50 monooxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase ( NQ01), three glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and two ar ylamine N-acetyltransferases (NAT1 and NAT2). We analysed DNA from tumour a nd nontumoural kidney tissue from 195 CCRCC patients. Single VHL mutations were identified in 88 patients and double mutations were present in two pat ients. Nine of 18 transversions were GC to TA, four were AT to TA, four wer e GC to CG and one was AT to CG. Ten of 19 transitions were GC to AT and ni ne were AT to GC. We also identified 53 frameshifts and two GC to AT at CpG . An excess of transversions was observed in a subset of patients with acti ve GSTT1 [GSTT1 (+) genotype] and probably defective NAT1 (NAT1 S/R variant genotype). All 18 transversions were in GSTT1 (+) patients, whereas only 7 6% of transitions (P=0.05) and 81%, of the other mutations (P=0.06) occurre d in this genotype. We found that 28% of the transversions were in the NAT1 S/R genotype versus 12% of the transitions (P=0.40) and 4% of the other mu tations (P=0.01). This suggests that pharmacogenetic polymorphisms may be a ssociated with the type of acquired VHL mutation, which may modulate CCRCC development. Pharmacogenetics 11:521-535. (C) 2001 Lippincott Williams & Wi lkins.