Esophageal Squamous Cell Carcinoma Susceptibility Research Articles

DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang, China

To investigate the role of metabolic enzyme and DNA repair genes in susceptibility of esophageal squamous cell carcinoma (ESCC). A case-control study was designed with 454 samples from 128 ESCC patients and 326 gender, age and ethnicity-matched control subjects. Genotypes of 69 single nucleotide polymorphisms (SNPs) of metabolic enzyme (aldehyde dehydrogenase-2, ALDH2; alcohol dehydrogenase-1 B, ADHB1; Cytochrome P450 2A6, CYP2A6) and DNA repair capacity genes (excision repair cross complementing group 1, ERCC1; O(6)-methylguanine DNA methyltransferase, MGMT; xeroderma pigmentosum group A, XPA; xeroderma pigmentosum group A, XPD) were determined by the Sequenom MassARRAY system, and results were analyzed using unconditional logistic regression adjusted for age, gender. There was no association between the variation in the ERCC1, XPA, ADHB1 genes and ESCC risk. Increased risk of ESCC was suggested in ALDH2 for frequency of presence C allele of SNP [Rs886205: 1.626 (1.158-2.284)], XPD for C allele [Rs50872: 1.482 (1.058-2.074)], and MGMT for A allele [Rs11016897: 1.666 (1.245-2.228)]. Five variants of MGMT were associated with a protective effect on ESCC carcinogenesis, including C allele [Rs7069143: 0.698 (0.518-0.939)], C allele [Rs3793909: 0.653 (0.429-0.995)], A allele [Rs12771882: 0.719 (0.524-0.986)], C allele [Rs551491: 0.707 (0.529-0.945)], and A allele [Rs7071825: 0.618 (0.506-0.910)]. At the genotype level, increased risk of ESCC carcinogenesis was found in homozygous carriers of the ALDH2 Rs886205 [CC vs TT, odds ratios (OR): 3.116, 95% CI: 1.179-8.234], MGMT Rs11016879 (AA vs GG, OR: 3.112, 95% CI: 1.565-6.181), Rs12771882 (AA vs GG, OR: 2.442, 95% CI: 1.204-4.595), and heterozygotes carriers of the ALDH2 Rs886205 (CT vs TT, OR: 3.930, 95% CI: 1.470-10.504), MGMT Rs11016879 (AG vs GG, OR: 3.933, 95% CI: 2.216-6.982) and Rs7075748 (CT vs CC, OR: 1.949, 95% CI: 1.134-3.350), respectively. Three variants were associated with a protective effect on ESCC carcinogenesis, carriers of the MGMT Rs11016878 (AG vs AA, OR: 0.388, 95% CI: 0.180-0.836), Rs7069143(CT vs CC, OR: 0.478, 95% CI: 0.303-0.754) and Rs7071825 (GG vs AA, OR: 0.493, 95% CI: 0.266-0.915). Increased risk of ESCC metastasis was indicated in MGMT for frequency of presence C allele [Rs7068306: 2.204 (1.244-3.906)], A allele [Rs10734088: 1.968 (1.111-3.484)] and C allele [Rs4751115: 2.178 (1.251-3.791)]. Two variants in frequency of presence C allele of CYP2A6 [Rs8192720: 0.290 (0.099-0.855)] and A allele of MGMT [Rs2053139: 0.511 (0.289-0.903)] were associated with a protective effect on ESCC progression. Increased risk of ESCC metastasis was found in heterozygote carriers of the MGMT Rs7068306 (CG vs CC, OR: 4.706, 95% CI: 1.872-11.833). Polymorphic variation in ALDH2, XPD and MGMT genes may be of importance for ESCC susceptibility. Polymorphic variation in CYP2A6 and MGMT are associated with ESCC metastasis.

Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease. We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions. We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these. We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.

Polymorphism in COX-2 modifies the inverse association between Helicobacter pyloriseropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study

BackgroundOverexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC.MethodsOne hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression.ResultsIn analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 – 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 – 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 – 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 – 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 – 0.47, p for multiplicative interaction 0.008)ConclusionH. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus.

Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma

Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis and cytokine expression. We aimed to evaluate association of COX-2 polymorphisms with predisposition to esophageal squamous cell carcinoma (ESCC), its phenotype variability and modulation of environmental risk in northern Indian population. We genotyped 174 patients with ESCC and 216 controls for COX-2 gene polymorphisms (−765G>C; −1195G>A; −1290A>G; 3′UTR 8473T>C) using PCR-RFLP. Data were statistically analyzed using chi-square test and logistic regression model. COX-2 −765C allele carriers were at increased risk for ESCC (OR = 1.66; 95% CI = 1.08–2.54; P = 0.004). However, −1195G>A; −1290A>G; 3′UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with ESCC. We observed significantly enhanced risk for ESCC due to interaction between COX- 2 −1195GA × −765GC + CC genotypes (OR = 4.60; 95% CI = 1.63–13.01; P = 0.004). High risk to ESCC was also observed with respect to COX-2 haplotypes, A −1290G −1195C −765T 8473 and A −1290A −1195C −765T 8473 [OR = 3.35; 95% CI = 0.83–13.44; P = 0.089; OR = 4.28; 95% CI = 0.43–42.40; P = 0.246] however, it was not statistically significant. Stratification of subjects based on gender showed that females were at higher risk for ESCC due to COX-2 −765C carrier genotypes (OR = 2.97; 95% CI = 1.23–7.18; P = 0.016). In association of genotypes with clinical characteristics, −765C carrier genotype conferred risk of ESCC in middle third of esophagus (OR = 1.78; 95% CI = 1.08–2.93; P = 0.023). In case-only analysis, interaction of environmental risk factors and COX-2 genotypes did not further modulate the risk for ESCC. In summary, COX-2 −765G>C polymorphism confers ESCC susceptibility particularly in females and patients with middle third anatomical location of the tumor. Interaction of COX-2 −1195GA and −765C carrier genotypes also modulates ESCC risk.

Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and human esophageal squamous cell carcinoma susceptibility.

Many human cancers are caused by synthetic or natural chemical compounds in the environment. Esophageal squamous cell carcinoma has been reported to be epidemiologically associated with tobacco and alcohol consumption. We studied the association between genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and esophageal squamous cell carcinoma susceptibility. We examined genetic polymorphisms of the CYPIA1, GSTM1, CYPIIE1, ADH2, and ALDH2 genes in 94 Japanese patients with esophageal squamous cell carcinoma and 70 unrelated healthy Japanese persons. There were no significant differences between healthy controls and patients with esophageal cancer in the polymorphisms of the CYPIA1, GSTM1, and CYPIIE1 genes. On the other hand, there were significant differences in the ADH2 and ALDH2 polymorphisms between healthy controls and esophageal cancer patients. The ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) genotypes were independently and significantly higher in esophageal cancer patients than in healthy controls. Furthermore, persons with the combined genotypes ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) were at extraordinarily high risk for esophageal squamous cell carcinoma, with an odds ratio of 17.9 (p < 0.001). Thus polymorphisms of alcohol-metabolizing enzymes, that is, ADH2 and ALDH2, may be useful for screening patients at high risk for esophageal cancer, which might facilitate clarification of esophageal tumorigenesis and prevention of esophageal cancer.