Original ArticlesAssociation of GSTT1 non-null and NAT1 slow/rapid genotypes with von Hippel-Lindau tumour suppressor gene transversions in sporadic renal cell carcinomaGallou, Catherinea*; Longuemaux, Sandrined*; Deloménie, Claudined; Méjean, Arnaudb; Martin, Natachaa; Martinet, Stéphanea; Palais, Gaëla; Bouvier, Raymondee; Droz, Dominiquec; Krishnamoorthy, Rajagopald; Junien, Claudinea; Béroud, Christophea; Dupret, Jean-MariedAuthor Information aINSERM U383, bService d'Urologie, cService d'Anatomie et de Cytologie Pathologique, Hôpital Necker-Enfants Malades, Paris, France, dINSERM U458, Hôpital Robert Debré, Paris, France and eLaboratoire d'Anatomie Pathologique, Hôpital Edouard Herriot, Lyon, France Received 10 October 2000; accepted 16 January 2001 Correspondence to Jean-Marie Dupret, CNRS UMR 7000, Faculté de Médecine Pitié-Salpêtrière, 105 boulevard de l'Hôpital, 75013 Paris, France Tel: +33 1 53 60 08 03; fax: +33 1 53 60 08 02; e-mail: [email protected] *C. Gallou and S. Longuemaux contributed equally to this work. Pharmacogenetics: August 2001 - Volume 11 - Issue 6 - p 521-535 Buy Abstract The von Hippel-Lindau (VHL) tumour suppressor gene is commonly mutated in renal cell carcinoma of clear cell type (CCRCC). We investigated the possible relationship between VHL mutations in sporadic CCRCC and polymorphism of genes encoding enzymes involved in carcinogen metabolism: two cytochrome P450 monooxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase (NQO1), three glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and two arylamine N-acetyltransferases (NAT1 and NAT2). We analysed DNA from tumour and nontumoural kidney tissue from 195 CCRCC patients. Single VHL mutations were identified in 88 patients and double mutations were present in two patients. Nine of 18 transversions were GC to TA, four were AT to TA, four were GC to CG and one was AT to CG. Ten of 19 transitions were GC to AT and nine 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 active GSTT1 [ GSTT1 (+) genotype] and probably defective NAT1 (NAT1 S/R variant genotype). All 18 transversions were in GSTT1 (+) patients, whereas only 76% of transitions (P = 0.05) and 81% of the other mutations (P = 0.06) occurred 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 mutations (P = 0.01). This suggests that pharmacogenetic polymorphisms may be associated with the type of acquired VHL mutation, which may modulate CCRCC development. © 2001 Lippincott Williams & Wilkins, Inc.