title: Association between NAD(P)H: quinone oxidoreductase 1 (NQ01) inactivating C609T polymorphism and adenocarcinoma of the upper gastrointestinal tract.
abstract: NQO1 is an antioxidant enzyme, important in the detoxification of environmental carcinogens. A single nucleotide polymorphism (C-->T) at position 609 of the NQO1 cDNA has been associated with susceptibility to tumours induced by chemical carcinogens. In our case-control study, we determined the prevalence of the C609T NQO1 polymorphism by PCR-RFLP analysis in Caucasian patients with oesophageal adenocarcinoma (OAC; n=61), cardiac adenocarcinoma (CAC; n=120) or gastric adenocarcinoma (GAC; n=203) vs. a control group that consisted of 252 healthy blood donors. Additionally, NQO1 mRNA expression and NQO1 protein expression were determined by RT-PCR and immunohistochemistry in a subset of cases. The NQO1 C609T genotype distribution was significantly different among controls (C/C, 73.4%; C/T, 25.0%; T/T, 1.6%) as compared to OAC patients (C/C, 49.2%; C/T, 47.5%; T/T, 3.3%; p=0.0004), CAC patients (C/C, 55.8%; C/T, 40.0%; T/T, 4.2%; p=0.0005) and with GAC patients (C/C, 65.5%; C/T; 30.6%, T/T; 3.9%; p=0.0377). The 609T allele overall frequency was 0.141 in controls, 0.270 in OAC patients, 0.241 in CAC patients and 0.192 in GAC patients. Individuals carrying 1 or 2 609T alleles had a 2.85-fold higher risk (95% CI: 1.61-5.07; p=0.0003) for the development of OAC and a 2.18-fold higher risk (95% CI: 1.38-3.44; p=0.0007) for the development of CAC than wild-type gene homozygotes. Immunohistochemical analysis showed NQO1 protein expression in 133 carcinomas, whereas 17 carcinomas were negative. Negativity for NQO1 protein expression correlated strongly with the NQO1 genotype being present in 3.9% of cases with C/C, 13.9% of cases with C/T and 62.5% of cases with T/T genotype (p<0.001). In contrast, NQO1 mRNA expression was detectable irrespective of underlying genotype. In conclusion, determination of the NQO1 genotype may gain importance as a stratification marker in future prevention trials for adenocarcinoma of upper gastrointestinal tract.
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D005764:Gastroesophageal Reflux / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D016017:Odds Ratio; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human