Cyclin D1 polymorphism (G870A) and susceptibility to gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma: a case-control study

AG Casson FRCSC^a,b, Z Zheng MD^b, SC Evans BSc^b, PJ Veugelers PhD^c, GA Porter MD^a, DL Guernsey PhD^a,b

^aDepartment of Surgery, ^bPathology, ^cCommunity Health and Epidemiology; Dalhousie University, Halifax, Nova Scotia, Canada

AIM: To investigate individual susceptibility to gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE) and primary esophageal adenocarcinoma (EADC), we studied the frequency of a polymorphism (G870A) in exon 4 of the cyclin D1 gene (CCND1), a cell cycle and DNA repair-associated gene recently implicated in the molecular pathogenesis of esophageal cancer. METHODS: Between 02/2001 and 02/2003, a total of 431 individuals were enrolled in a case-control study to evaluate lifestyle risk factors and molecular alterations in GERD (n=142), BE (n=130), and EADC (n=57), defined according to strict clinicopathologic criteria. Controls comprised 102 healthy, asymptomatic individuals from the same geographic region. Blood samples were obtained, with informed consent, and genomic DNA successfully extracted from patients with GERD (n=126), BE (n=125), EADC (n=56) and controls (n=95). Polymerase chain reaction (PCR) was used to amplify exon 4 of CCND1 and after digestion with BsrI, acrylamide gel electrophoresis was used to identify wild-type and the common G870A polymorphic allele. The presence of alleles (GG, GA, AA) was compared between cases (GERD, BE, EADC) and controls using logistic regression analysis to calculate age and gender adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared to controls, statistically significant differences were found for the AA genotype in patients with GERD (OR 2.83, CI 1.09-7.34), BE (OR 3.69, CI 1.46-9.29), and EADC (OR 5.99, CI 1.89-18.96). In contrast, no substantial variation was observed for the GG and GA genotypes across controls, patients with GERD, BE or EADC. CONCLUSIONS: We conclude that the CCND1 polymorphism G870A is associated with increased risk for GERD, BE and EADC in this population. The contribution of this polymorphism to individual susceptibility for progression to EADC suggests potential clinical application in Barrett’s surveillance programs.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 897 (Precursor lesions).