BACKGROUND Familial clustering has been reported in gastric cancer (GC). However, the mechanism of the intrafamilial aggregation of GC remains unclear.

METHODS This study enrolled 123 GC relatives and their age-matched and sex-matched controls without a family history of GC, and 639 patients with GC (intestinal or diffuse type). Residence during childhood, socioeconomic status, and smoking habits were investigated as environmental factors, Helicobacter pylori (H. pylori) virulence factors (cagA, vagA s1 and m1 regions, and oipA) were evaluated, and seven biallelic polymorphisms (IL-1B-511, TNF-A-308, IL-6-572, IL-8-251, IL-10-592, IL-10-1082, and TGFB1-509) and IL-1RN variable number of tandem repeats were genotyped.

RESULTS For the group without GC, intestinal metaplasia (IM) at corpus was more prevalent in GC relatives than in controls in the age of less than 50 years [grade of IM (mean±standard deviation), 0.02±0.15 in controls vs. 0.22±0.56 in GC relatives, P=0.018]. cagA, vagA s1 and m1, and oipA positives showed an increase in GC relatives among current H. pylori-infected patients, which did not reach a statistical significance. Among intestinal-type GC patients, multivariate analyses showed that residence in a rural area during childhood (odds ratio: 2.03; 95% confidence interval: 1.05-3.95) and TGFB1-509 T (odds ratio: 0.47; 95% confidence interval: 0.26-0.88) were associated with a positive family history of GC; however, it showed only insignificant results in diffuse-type GC.

CONCLUSION The intrafamilial aggregation of GC might be associated with environmental factors during childhood or TGFB1-509 genetic polymorphism, or possibly H. pylori virulence. These factors may promote IM and development of intestinal-type GC.