Hai-Xia Cao

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 (kg * years) 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 (kg * years). 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 (kg * years), drinkers carrying both ALDH2 A and ADH2 G alleles and with a cumulative amount of alcohol consumption ⩾2.5 (kg * years) 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.

Relationship between growth hormone 1 genetic polymorphism and susceptibility to colorectal cancer.

The aim of this study was to evaluate the relationship between smoking, alcohol drinking and genetic polymorphism of the growth hormone 1 gene (GH1) T1663A with reference to colorectal cancer. We conducted a case–control study with 315 cases of colorectal cancer and 438 population-based controls in the Jiangsu Province, China. GH1 T1663A genotypes were identified using PCR–RFLP (restriction fragment length polymorphism) methods. Information on smoking and drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model. The distribution of T/T and A/A genotypes was significantly different between controls and cases (χ2MH=3.877, P=0.049). Compared with the GH1 T/T genotype, the A/A genotype was at a decreased risk of developing colorectal cancer (sex-, age-, body mass index-, smoking- and alcohol drinking-adjusted OR=0.56, 95% confidence interval: 0.34–0.90). Smoking was not associated with the risk of colorectal cancer, whereas alcohol drinking was associated with an increased risk of colorectal cancer. Among nonsmokers or nondrinkers, individuals who had the GH1 A/A genotype were at a decreased risk of developing colorectal cancer compared with individuals who had the GH1 T allele. These results show that the GH1 T1663A A/A genotype can decrease the risk for colorectal cancer.

Genetic polymorphisms in methylenetetrahydrofolate reductase and clinical response to chemotherapy in non-small cell lung cancer

BACKGROUND Methylenetetrahydrofolate reductase (MTHFR) plays an important role in metabolism of folate and DNA methylation. In vitro, many studies have demonstrated that abnormal methylation of some genes may affect the sensitivity of tumor cells to cytotoxic drugs and agents interfering with DNA synthesis. The aim of this study is to investigate the relationship between genetic polymorphisms of MTHFR C677T or A1298C and the response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC). METHODS A total of 97 patients with NSCLC were analyzed. MTHFR genotypes were detected in all the patients by PCR-RFLP method. All the patients were treated with platinum-based chemotherapy. RESULTS (1) Out of all the cases, the frequencies of MTHFR C677T C/C, C/T and T/T genotypes were 34.0%, 50.5% and 15.5%, respectively, while the frequencies of MTHFR A1298C A/A, A/C and C/C genotypes were 64.6%, 29.2% and 6.3%, respectively. The overall response rate (complete and partial response) to platinum-based chemotherapy was 39.2%. (2) No significant difference in response rate to chemotherapy was observed according to the MTHFR C677T or A1298C genotypes. However, MTHFR C677T and A1298C polymorphisms showed a synergic effect on chemotherapeutic efficacy, the response rate of patients with MTHFR C677T T allele and A1298C A/A genotype (51.1%) was significantly higher than those with MTHFR C677T C/T and A1298C C allele (12.5%)(P=0.007, OR=7.30, 95% CI: 1.34-52.47). CONCLUSIONS The results suggest that the synergic effect between MTHFR C677T and A1298C polymorphisms is associated with clinical response to platinum-based chemotherapy. Detection of MTHFR genotypes may indicate the sensitivity of NSCLC patients to platinum-based chemotherapy.

Growth Hormone 1 T1663A Polymorphism, Recreational Physical Activity and BMI, and Breast Cancer Risk in Chinese Women.

To evaluate the relationship between the growth hormone 1 (GH1) T1663A polymorphism, recreational physical activity and body mass index (BMI) with reference to breast cancer, we conducted a case-control study with 669 cases of breast cancer and 682 population-based controls in Jiangsu Province, China. A structured questionnaire was used to elicit detailed information. All subjects completed an in-person interview. GH1 genotypes were identified using PCR-RFLP methods. Odds ratios (ORs) were estimated with an unconditional logistic model. The distribution of GH1 genotypes was not significantly different between controls and cases (χ2=2.576, P=0.276). Results of stratified analysis by the participation status of the recreational physical activity showed that the persons with GH1 A allele were at a decreased risk of breast cancer (adjusted-OR=0.66; 95% CI, 0.50-0.87) only among inactive individuals. Stratified analysis by BMI showed that the genotype A/A was associated with a decreased risk of breast cancer only among individuals of the BMI<25 (adjusted-OR=0.80; 95% CI, 0.66-0.98). The findings of this study suggest that recreational physical activity and BMI may modify any association between the GH1 T1663A polymorphism and breast cancer risk.