CDH1 c‐160a promotor polymorphism is not associated with risk of stomach cancer

Abstract

We have combined data from case control studies designed to test the hypothesis that the c-160a promotor polymorphism in the gene coding for the cell adhesion molecule E-cadherin (CDH1) is associated with stomach cancer. A total of 899 individuals (433 patients and 466 controls) were analyzed. The genotype frequencies did not differ significantly between cases and controls, and the genotype-specific risks were not significantly different from unity, with an odds ratio for heterozygotes compared with the common homozygote of 1.3 (95% CI 0.98 -1.8) and 1.2 (0.68 -2.0) for rare homozygotes compared with common homozygotes. We found no evidence for differences in risk for the intestinal-and diffusetype histopathologic subgroups. © 2002 Wiley-Liss, Inc. Key words: stomach cancer; CDH1; polymorphism; susceptibility E-cadherin plays a critical role in many aspects of cell adhesion, epithelial development and the establishment and maintenance of epithelial polarity. Somatic mutations in the E-cadherin gene (CDH1) have been identified in about 50% of sporadic diffuse gastric tumors and lobular breast cancers, and protein truncating, germline mutations in CDH1 confer a high risk of diffuse gastric cancer, with the gene acting as a classic tumor supressor. [1][2][3][4] Several polymorphisms have been identified in CDH1, 1 of which, c-160a, has been shown to have a functional effect. The a-allele has been shown to decrease the transcriptional efficiency by 68% compared with the c-allele. 5 However, a more recent study reported no association between the a-allele risk of breast cancer and found that that the effect of the a-allele on transcription was small. 6 Nevertheless, this polymorphism is a good candidate for susceptibility to stomach cancer, and we have combined the data from 3 separate, small case-control studies to test this hypothesis. MATERIAL AND METHODS Cases and controlsCanadian study. Gastric cancer cases were identified through a search of the pathology archives of the Vancouver Hospital. Cases were selected for analysis if they had either lymph nodes or mucosal margins that were negative for malignancy (n ϭ 148). The mean age of the cases was 65 years (range 23-86 years). DNA was extracted from histologically normal paraffin-embedded tissue using a Qiagen kit (Hilden, Germany). Germline DNA from 93 anonymous normal controls was obtained from a pediatric molecular diagnostics laboratory.The E-cadherin gene promoter polymorphism c-160a was detected by restriction fragment length polymorphism (RFLP) analysis of a 189 bp DNA fragment amplified from the E-cadherin gene proximal promoter region. The PCR amplicon was obtained using the previously published primers 5Ј-TCCCAGGTCTTAGT-GAGCCA-3Ј and 5Ј-GGCCACAGCCAATCAGCA-3Ј and cycling conditions. 5 The PCR products were digested with BstE2 and Af III. BstE2 specifically cleaves fragments with the c-allele, and Af lII specifically cleaves fragments with the a-allele. The fragments were discriminated on a 3% agarose gel.German study. Eligible cases (n ϭ 133) were tho...

Analysis of Ethnic Admixture in Prostate Cancer

“…In contrast, Humar et al [34] described the association of the mutant A allele with sporadic diffuse gastric cancer in Italy. No association was found between À160C/A genotype and risk of stomach cancer in three populations of European origin, namely Canadians, Germans, and Portuguese [31]. In urothelial cancer, however, Japanese individuals carrying the AA genotype had a 2.3-fold increased risk of being affected by the disease than CC individuals, although no correlation with tumor progression was detected [32].…”

“…The association among Jamaicans should be considered with caution since IVS1 þ 6T/C was noticeably out of Hardy-Weinberg equilibrium. The frequency of the A allele in European American controls was lower than that reported for most European populations in other PCA studies [16][17][18] or non-PCA studies [31,34], but was comparable to Japanese population frequencies [20,32]. With the exception of SNP À160C/A, we found significant differences between ethnicities in genotype and allele frequencies of all CDH1 markers.…”

A Single Nucleotide Polymorphism in the E-cadherin Gene Promoter-160 is Not Associated with Risk of Korean Gastric Cancer

“…Thus, A-type promoter variant may be regarded as a candidate cancer susceptibility polymorphism. However, recent epidemiological studies failed to demonstrate a correlation between the E-cadherin promoter variant and breast (19) or colorectal cancer (20) or gastric cancer (15). In the present study, there is no significant difference in the Ecadherin -160 promoter genotype between normal healthy individuals and gastric cancer patients (Table 1).…”

“…However, It has been reported that the A allele was suggested to be protective against gastric cancer in Taiwanese (14) and that the -160 promoter polymorphism is not associated with risk of gastric cancer (15). Thus, it is worthwhile to investigate the genotype specific risk of -160 promoter polymorphism in Korean gastric cancer patients.…”

E‐cadherin polymorphism −160 C/A and prostate cancer

“…4,5 An open question remains the inverse relation (AA as protective or risk genotype) between cancer and controls comparing PCa (the study of Verhage et al 1 and our study) and gastric cancer studies. 5,6 The TaqMan assay on demand proved robust and useful. It allowed easy determination of the alleles and it saved the considerable amount of time normally required to set up the assay because the only variable that needs to be adjusted is the amount of DNA that is allowed for in broad boundaries.…”