Jian-Zhong Wu

HOGG1 Ser326Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese

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, Ser326Cys, 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 Ser326Cys 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.

Glutathione-S-transferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case-control study of a high-incidence area in Jiangsu Province, China

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.

Dietary Protective and Risk Factors for Esophageal and Stomach Cancers in a Low‐epidemic Area for Stomach Cancer in Jiangsu Province, China: Comparison with Those in a High‐epidemic Area

Comparative epidemiological studies with ecological and case‐control approaches in high‐ and low‐epidemic areas of China have provided us with much evidence with regard to risk and benefit in the environment. To clarify how dietary factors are involved in esophageal and stomach cancer development, we performed a case‐control study in a low‐epidemic area, and compared the findings with those obtained earlier for a high‐epidemic area for stomach cancer in the same Jiangsu Province, China. We recruited 199 and 187 cases with esophageal and stomach cancers, respectively, and 333 population‐based common controls. Odds ratios (ORs) for esophageal and stomach cancers were calculated with adjustment for potential confounding factors, using an unconditional logistic model. Current and former smoking elevated the OR for esophageal cancer, along with high intake of pickled vegetables and broiled meat, while decreased ORs were observed for frequently consumed raw vegetables and garlic. With regard to stomach cancer, ORs were increased with frequent consumption of salty fish, leftover gruel, and broiled meat, and lowered by snap bean consumption. The present risk factors were common to the previously obtained results in the high‐epidemic area, and similarly distributed in each general population. While more protective factors were observed in the high‐epidemic area, their penetrance was much greater in the low‐epidemic area. The present study thus suggests that frequent vegetable and garlic consumption contributes to low mortality rates for esophageal and stomach cancers in a low‐epidemic area, counteracting similar exposure levels for risk factors as in the high‐epidemic area .

Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China

Germline mutations in MSH2, MLH1, E‐cadherin and MutY (MYH) genes have been implicated in the occurrence of gastric cancer (GC). Epidemiological investigation was performed by recruiting patients with GC onset during 2002 in Jiangsu province, China. We identified suspected hereditary GC patients based on either the GC family history or GC onset at early ages. We have screened germline variations in 101 suspected hereditary GC patients at the coding sequences of MSH2, MLH1, E‐cadherin and MYH genes with polymerase chain reaction‐denaturing high‐performance liquid chromatography (PCR‐DHPLC) analysis and DNA sequencing. The result showed that about 40% of patients carried germline variations, predominantly with missense mutations. Of the variations detected are 2 base pair substitutions, c.53C > T and c.74G > A, which is predicted to generate missense mutations of p.Pro18Leu and p.Gly25Asp, respectively, and occurred at the same allele of MYH gene. The frequency of variant haplotype T/A in patients was higher than that in the control group (p = 0.021, odds ratio [OR] = 4.43, 95% confidence interval [95% CI] = 1.33–14.72). Difference in the frequency of the silent mutation p.Asn751Asn in E‐cadherin gene was also found between patients and controls (p = 0.009, OR = 2.54, 95% CI = 1.30–4.95). Moreover, 6 types of variations were detected in MSH2 and MLH1 genes in 14 of 101 patients. Most of them occurred at exon7 of MSH2, frequently c.1168C > T, resulting in mutation of p.Leu390Phe. In summary, germline mutation at MSH2, MLH1, E‐cadherin and MYH genes is a frequent event in the familial GC. They may form a genetic basis for the familial GC susceptibility in Chinese population.

Polymorphism in the 3'-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy.

AbstractTo investigate the relationship between polymorphism in the 3′-untranslated region (3′-UTR) of the thymidylate synthase (TS) gene and sensitivity of gastric cancer to 5-fluorouracil (5-FU)-based chemotherapy, 106 cases of advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy; DNA from peripheral blood leukocytes was obtained before therapy. TS 3′-UTR genotypes were detected by PCR-RFLP. Polymorphism in the TS 3′-UTR can be classified into three groups according to the presence or absence of a 6 bp nucleotide fragment: the −6/−6 bp, −6/+6 bp and +6/+6 bp groups. The response rate of the −6/−6 bp and −6/+6 bp groups was found to be significantly higher than the +6/+6 bp group. These results show that the presence of the TS 3′-UTR 6 bp nucleotide fragment can be correlated with the sensitivity of gastric cancer to 5-FU-based chemotherapy, and that the TS 3′-UTR polymorphism profile can be used to guide the choice of 5-FU-based chemotherapy in advanced gastric cancer.

MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women.

To evaluate the relationship between dietary folate intake and genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) with reference to breast cancer risk, we conducted a case–control study with 669 cases and 682 population-based controls in the Jiangsu Province of China. MTHFR C677T and A1298C genotypes were identified using PCR–RFLP (restrictrion fragment length polymorphism) methods. Dietary folate intake was assessed using an 83-item food frequency questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model. The frequencies of MTHFR C677T C/C, C/T and T/T genotypes were 32.37, 48.88 and 18.75% in cases and 37.66, 48.24 and 14.10% in controls, respectively. The difference in distribution was significant (χ2=6.616, P=0.037), the T/T genotype being associated with an elevated OR (adjusted for age, menopausal status, body mass index (BMI), income, work intensity and status of smoking and drinking) for breast cancer (1.62, 95% confidence interval (95% CI): 1.14–2.30). The frequencies of MTHFR A1298C A/A, A/C and C/C were 71.47, 27.08 and 1.44% in cases and 68.11, 30.13 and 1.76% in controls, respectively, with no significant differences being found (χ2=1.716, P=0.424). A significant inverse relationship was observed between folate intake and breast cancer risk. Compared with the lowest tertile of folate intake, the adjusted OR for breast cancer in the top tertile was 0.70 (95% CI: 0.53–0.92). However, no significant interaction was observed between folate intake and the MTHFR C677T polymorphism. Among individuals with the MTHFR A1298C A/A genotype, adjusted ORs for breast cancer were 0.89 (0.62–1.27) and 1.69 (1.20–2.36) for the second to the third tertile of folate intake compared with the highest folate intake group (tread test, P=0.0008). The findings of this study suggest that MTHFR genetic polymorphisms and dietary intake of folate may modify susceptibility to breast cancer.

Polymorphisms in XRCC1 gene, alcohol drinking, and risk of colorectal cancer: a case-control study in Jiangsu Province of China.

To evaluate the relationship between alcohol drinking, XRCC1 codon 194 and 399 polymorphisms and risk of colorectal cancer, we conducted a case-control study with 315 colorectal cancer cases (105 colon, 210 rectal) and 439 population-based controls in Jiangsu Province of China. The XRCC1 codon 194 and 399 genotypes were identified using polymerase chain reaction and restrictrion fragment length polymorphism methods (PCR-RFLP). A structured questionnaire was used to elicit detailed information. Odds ratios (ORs) were estimated with an unconditional logistic model. In this study no significant differences were observed among the studied groups with regard to the genotype distribution of the XRCC1 codons 194 and 399 and the risk of colorectal cancer did not appear to be significantly influenced by genotype alone, whereas alcohol consumption showed a positive association (P for trend <0.01). When combined effects of XRCC1 polymorphisms and alcohol consumption were analyzed, we found that the 194Trp or 399Gln alleles further increased the colorectal cancer risk due to high alcohol intake. These findings support the conclusion that colorectal cancer susceptibility may be altered by gene-environment interactions.

Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk for esophageal cancer in a Chinese population

To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption and the susceptibility to esophageal cancer in a Chinese population, we conducted a case–control study with 221 cases and 191 population-based controls in the Taixing city of Jiangsu Province of China. ADH2 and ALDH2 genotypes were examined using PCR and denaturing high-performance liquid chromatography. Alcohol drinkers with the ALDH2 A allele showed a significantly increased risk of esophageal cancer compared with drinkers with the ALDH2 G/G genotype (odds ratio (OR)=3.08, 95% confidence interval (CI): 1.65–5.78) or nondrinkers with any genotype (OR=3.05, 95% CI: 1.49–6.25). Drinkers with the ALDH2 A allele and a cumulative amount of alcohol consumption ⩾2.5 (kgu2009*u2009years) were at a significantly higher risk of developing esophageal cancer (OR=11.93, 95% CI: 3.17–44.90) compared with individuals with ALDH2 G/G genotypes and a cumulative amount of alcohol consumption <2.5 (kgu2009*u2009years). A dose-dependent positive result was found between cumulative amount of alcohol consumption and risk of esophageal cancer in individuals carrying the ALDH2 A allele (P=0.023) and the homozygous ALDH2 G allele (P=0.047). Compared with individuals carrying both ALDH2 G/G and ADH2 A/A alleles and with a cumulative amount of alcohol consumption <2.5 (kgu2009*u2009years), drinkers carrying both ALDH2 A and ADH2 G alleles and with a cumulative amount of alcohol consumption ⩾2.5 (kgu2009*u2009years) showed a significantly elevated risk of esophageal cancer (OR=53.15, 95% CI: 4.24–666.84). This result suggests that to help lower their risk for esophageal cancer, persons carrying the ALDH2 A allele should be encouraged to reduce their consumption of alcoholic beverages.

Abortions and breast cancer risk in premenopausal and postmenopausal women in Jiangsu Province of China.

To evaluate the relationship between abortions and risk of breast cancer, we conducted a case-control study with 669 cases and 682 population-based controls in Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. Unconditional logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The results have revealed that induced abortion was related to increased risk of breast cancer. Premenopausal women who had ≥ 3 times of induced abortion were at increased crude OR (2.41, 95%CI: 1.09-5.42) and adjusted-OR (1.55, 95%CI: 1.15-5.68). Postmenopausal women with a previous induced abortion were at increased crude OR (2.04, 95%CI: 1.48-2.81) and adjusted-OR (1.82, 95%CI: 1.30-2.54), and there was a significant increase trend in OR with number of induced abortions (p for trend: 0.0001). Overall, spontaneous abortion did not significantly alter the risk of breast cancer, but postmenopausal women who had history of spontaneous abortion were at increased OR. These results suggested that relationship between breast cancer and abortions may depend on menopausal status and induced abortion may played an important role in the development of breast cancer in Jiangsu women of China.

Polymorphisms in the Thymidylate Synthase Gene and Risk of Colorectal Cancer

To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5-UTR and 6-bp ins/ del in 3-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, we conducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsu province, China. TS genotypes were identified using PCR-RFLP (restriction fragment length polymorphism) methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that the distributions of 5-UTR genotypes in TS were significantly different between controls and male colon cases (χ2 =8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk of colon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. In contrast, the 6-bp ins/del polymorphism at the TS 3- UTR did not influence risk of the colorectal, colon and rectal cancers. When combined genotypes for both TS 5-UTR and 3-UTR polymorphisms were evaluated, individuals with the 5-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men with the 3-UTR -6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences in TS 5-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS 3-UTR and 5-UTR polymorphisms in increasing risk of colon cancer among Chinese men.