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Aim: To investigate associations between the Rsa I polymorphism of CYP2E1 and risk of colorectal cancer., Methods: A case-control study was conducted with 315 colorectal cancer cases (105 colon, 210 rectal) and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1 by PCR amplification followed by digestion with Rsa I. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model., Results: The proportional distribution of the CYP2E1 Rsa I c1/c1, c1/c2 and c2/c2 genotypes were 61.4%, 35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8% in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant difference was noted between controls and rectal cancer cases (P = 0.029), the c2/c2 genotype being associated with elevated OR (adjusted age, sex and status of the smoking and alcohol drinking) for rectal cancer (1.64, 95% CI, 1.12-2.41, vs c1 allele carriers), but not for colon cancer. In interaction analysis between the CYP2E1 Rsa I genotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon (4.74, 95% CI, 1.10-20.40) and rectal (5.75, 95% CI, 1.65-20.05) cancers. Among non-smokers, the CYP2E1 Rsa I c2/c2 genotype was also associated with elevated ORs in the two sites (1.95, 95% CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99)., Conclusion: The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.

To evaluate interactions between lifestyle factors and glutathione-S-transferases M1 (GSTM1) and GSTT1 genotypes with reference to development of esophageal and stomach cancers, we conducted a case-control study of 141 cases of esophageal cancer, 153 cases of stomach cancer and 223 population-based controls in Huaian City of Jiangsu Province, China. GSTM1 and GSTT1 genotypes were identified by multiplex polymerase chain reaction. The GSTM1 null genotype was associated with an increased odds ratio for esophageal cancer (2.17, 95% confidence interval=1.35-3.50), but not for stomach cancer. A combined effect was also observed between smoking and the GSTM1 null genotype with regard to esophageal risk. Tea drinking was a protective factor for both cancers, its effect being independent of the GSTT1 and GSTM1 genotypes. These findings suggest the GSTM1 polymorphism is involved in the susceptibility to esophageal cancer development, and tea consumption reduces the risk of esophageal and stomach cancers.

Oxidative stress is involved in many types of DNA damage, e.g., resulting in 8-hydroxyguanine adducts. Since a human counterpart exists for the yeast gene OGG1 (hOGG1) encoding an enzyme that repairs 8-hydroxyguanine, its polymorphism, Ser(326)Cys, might have potential as a genetic marker for cancer susceptibility. To investigate its association with stomach cancer risk and possible interactions with environmental factors, we conducted a case-control study of 101 stomach cancer cases and 198 controls using PCR-single-strand conformation polymorphism and a questionnaire approach. The proportional distribution of the Cys/Cys alleles did not differ between stomach cancer cases and controls, but subgroup analyses revealed that a frequent drinking habit elevated the odds ratio (OR) for stomach cancer in Cys/Cys compared to Ser/Ser and Ser/Cys carriers. The ORs with frequent consumption of pickled vegetables and meat tended to be higher in Cys/Cys than in Ser/Ser and Ser/Cys carriers, these interactions being on the borderline of statistical significance. Our findings suggest that the hOGG1 Ser(326)Cys polymorphism may alter the impact of some environmental factors on stomach cancer development. For confirmation, an additional study with a larger number of subjects is now required., (Copyright 2002 Wiley-Liss, Inc.)

Because cytochrome P-450 2E1 (CYP2E1) is involved in metabolic activation of environmental chemical carcinogens, gene polymorphisms that alter its functions may be associated with cancer susceptibility. However, previous studies have revealed disconcordant results with regard to cancer risk. To investigate gene-environment interactions with the RsaI polymorphism of CYP2E1 in terms of risk of esophageal and stomach cancers, we conducted a case-control study with 93 esophageal and 98 stomach cancer cases and 196 population-based controls in a high-endemic area for these cancers of China. We assayed genomic DNA samples for RFLPs in the CYP2E1 by PCR amplification, followed by digestion with RsaI, and collected information on environmental factors by a questionnaire approach. Odds ratios were estimated with an unconditional logistic model, after adjustment for potential confounding factors. The proportional distribution of the homozygous common RsaI alleles did not differ between cancer cases of the esophagus (59.1%) and stomach (59.2%), and controls (61.7%). However, we found a significant positive interaction between the heterozygous and homozygous RsaI rare alleles and ever-smoking in the odds ratio for stomach cancer (P = 0.015). The interaction between the gene polymorphism and dietary factors, such as garlic consumption, was not observed in both cancer cases. These results suggest that gene-environment interactions between the CYP2E1 polymorphism and smoking may have the potential to alter the susceptibility for cancer development in the stomach.

EphB2, a member of the Eph receptor protein-tyrosine kinase family, is overexpressed in several human gastrointestinal tumors. Furthermore, the EphB2 gene is localized at 1p35-p36.1, a frequently deleted region in colon and other cancers. So, despite its overexpression in some kind of tumors, we decided to study the possibility of involvement in the EphB2 gene (EPHB2) mutation in colon cancers, because some of the well known tumor suppressor genes (e.g. p53) is overexpressed (really accumulated) in tumors. Fifty colon tumor samples of matched with their respective normal tissues, were studied for mutation of the EPHB2. Analysis of the genomic structure of EphB2 and survey of all 16 exons revealed an infrequent polymorphism (intron 2) and mutation (intron 8). Another polymorphism in exon 6, localized at nucleotide 1359 (A-->G) was found to be rather frequent in Japanese and Chinese subjects, but very rare in Caucasians. Taking advantage of this polymorphism within EPHB2, we surveyed the loss of heterozygosity (LOH) status of this gene in Japanese colorectal tumors. Among the 50 samples analyzed, 24 were informative, and LOH was found in five of the15 (33.3%) informative rectal cancer cases. Mutation analysis covering all 16 exons in the remaining allele did not reveal any mutations. Thus, EPHB2 is not a classical tumor suppressor gene.

Okinawa, a group of islands that lie between the East China Sea and the Pacific Ocean, 2000 km south of the Japanese main islands, has a different profile of diseases, ethnicities, and cultures than does the rest of Japan. We examined an Ile462Val polymorphism (CYP1A1*2 allele) of cytochrome P450 IA1 in a hospital-based case-control study of lung cancer patients (247 cases and 185 controls) in Okinawa to ascertain the association of this variant with lung cancer. In addition, the distribution of this genotype was studied in populations from different areas of Japan, including Tokyo (n = 69) and Iwate (northern part of Japan; n = 81), as well as in a Chinese group from the Jiangsu province (n = 39) and in an Australian Caucasian group (n = 146). Genotype frequency in controls was not significantly different from area to area in Japan. In Okinawa, however, the genotype encoding Val/Val was associated with a significantly higher risk of lung cancer (odds ratio = 3.32, P = 0.013), especially of squamous cell carcinoma and small cell carcinoma (odds ratio = 4.85 and 9.35, respectively). The Val-encoding allele was less frequent in the Chinese population and was rare in Australian Caucasians. Thus, this study gives support to the value of the cytochrome P450 IA1 Ile462Val polymorphism as a practical high-risk marker of lung cancer in populations, especially those in southeast Asia, in which this variant is more common.

Background: Linxian is the highest endemic area of esophageal squamous cell carcinoma (ESCC) in China and one of the highest incidence areas in the world. The relationship of p53 protein accumulation to geographic variation, pathologic findings, and prognosis has not been investigated extensively., Methods: Formalin fixed, paraffin embedded ESCC tissues from 100 patients who underwent esophagectomy between 1973 and 1983 were immunostained by using monoclonal antibody pAB1801., Results: p53 overexpression was observed in 41 (87.2%) of 47 tumors of patients in Linxian and in 16 (64%) of 25 additional patients outside Linxian. Its prevalence in the noncancerous epithelium (11/72, 15.3%) and carcinoma in situ (1/7, 14.3%) was lower than that in invasive lesions (64/93, 68.8%). Its immunostaining intensity increased with the depth of cancer invasion. Of 30 primary carcinomas with lymph node metastasis, 29 (96.7%) were positive. However, only 36 (51.4%) of 70 primary lesions without metastasis were positive, and a higher intensity was noticed in the metastases. There was a lower expression rate in tumors of patients surviving more than 10 years (25/52, 48.1%) than in those surviving less than 3 years (40/48, 83.3%). Overall and nonadvanced or metastasis-free cumulative survival rates were both significantly different in patients with and without p53 protein overexpression., Conclusions: There is a higher expression rate of p53 protein in ESCC in tumors of patients from Linxian than in those from the surrounding area. The accumulation of p53 protein is related to the invasiveness and capability for metastases of cancer cells and appears to be a useful prognostic factor for patients with ESCC.