No abstract

NQO1 is an antioxidant enzyme, important in the detoxification of environmental carcinogens. A single nucleotide polymorphism (C3 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,)16؍‬ cardiac adenocarcinoma (CAC; n‫)021؍‬ or gastric adenocarcinoma (GAC; n‫)302؍‬ 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,)4000.0؍‬ CAC patients (C/C, 55.8%; C/T, 40.0%; T/T, 4.2%; p‫)5000.0؍‬ and with GAC patients (C/C, 65.5%; C/T; 30.6%, T/T; 3.9%; p‫.)7730.0؍‬ 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)3000.0؍‬ for the development of OAC and a 2.18-fold higher risk (95% CI: 1.38 -3.44; p‫)7000.0؍‬ 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.

Aberrant promoter methylation is an important mechanism for gene silencing. In the present study, 50 Barrett's esophagus-associated esophageal adenocarcinomas (ADC), 50 cardiac ADC and 50 gastric ADC were investigated by means of methylation-specific real-time PCR for hypermethylation in the tumor suppressor genes APC, p16 INk4A Adenocarcinomas (ADC) of the esophagus and the stomach are characterized by important differences in etiological and clinical background. Whereas the incidence of esophageal ADC has increased in Western countries in the last 30 years, there has been a decrease in gastric ADC incidence during the whole 20th century. 1 Chronic gastroesophageal reflux disease and subsequent development of Barrett's esophagus on the one side and dietary factors, bile reflux and Helicobacter-pylori-infection on the other side are among the most important risk factors for esophageal or gastric ADC, respectively. 2,3 The position of cardiac ADC in this context is less clear. Although traditionally considered as a gastric carcinoma, cardiac ADC shares a number of features with esophageal ADC such as profound male predominance, rising incidence and etiological association with chronic gastroesophageal reflux. 4,5 Moreover, recent investigations using the comparative genomic hybridization technique showed that genetic aberrations in cardiac ADC are probably more closely correlated to esophageal than to gastric ADC. 6,7 However, the hypothesis that esophageal and cardiac ADC are probably one entity 5 has been contradicted by the results of others. 8 Aberrant DNA methylation is a common feature of human cancer. 9 -12 In recent years, a CpG island hypermethylation profile of tumors has emerged that indicates a tumor type specific methylation pattern at least for some tumor suppressor genes. 13,14 Concerning adenocarcinomas of the upper gastrointestinal tract, previous studies indicate that hypermethylation of the tumor suppressor genes APC and p16 INK4A are prevalent findings in esophageal 15,16 as well as in gastric ADC. 17,18 In contrast, hypermethylation of p14 ARF seems to be substantially less frequent in esophageal ADC 16 than in gastric ADC. 19,20 However, since methylation patterns of esophageal and gastric ADC have not yet been compared within one study, reported differences between both tumor types may be influenced by differences in the methods used for the detection of hypermethylation. Moreover, the prevalence of hypermethylation of APC, p16 INK4A and p14 ARF in cardiac ADC has not been investigated so far. Thus, it is currently unclear whether significant differences in methylation pattern of these tumor suppressor genes exist between esophageal, cardiac and gastric ADC. Furthermore, it is not known whether distinct methylation patterns exist in correlation with the predominant histological subtypes of upper gastrointestinal tract adenocarcinomas (diffuse subtype vs. gland-forming subtype) as it has been recently shown for histological subtypes of lung cancer 21 and breast cancer. 22 In our study, w...

Our results suggest that, in contrast to German Caucasians, the MTHFR 677CC homozygous wild-type plays a protective role in the development of ESCC in the northern Chinese population.

Our results show that frequencies of p16 or cyclin D1 polymorphisms in gastric and esophageal ADC do not differ significantly from the healthy control group. Therefore, these polymorphisms are unlikely to be associated with risk of ADC of the upper gastrointestinal tract.