D-amino acid oxidase (DAO) rare genetic missense variant p.Pro103Leu and gastric cancer

Gastric cancer is prevalent in the Asian population. Genetic predisposition to gastric cancer is not fully understood. Recent studies have demonstrated that D-amino acid oxidase (DAO), a multifunctional enzyme, protects the mucosa of gastrointestinal (GI) tracts by generating hydrogen sulfide (H(2)S) in the stomach of rodents. The present study surveyed rare germline variants in the human DAO gene with regard to the incidence of gastric cancer. The consecutive autopsy cases registered in the JG-SNP database (n=2,343; mean age, 80 years) were employed and genotyped with Exome Bead-Chips. There were three non-synonymous rare variants, p.R22H, p.P103L and p.R283Q, of which the minor allele frequencies were 0.09, 0.21 and 0.02%, respectively. Carriers of these variants were surveyed, the results of which revealed that 4 out of 10 patients with the p.P103L variant had gastric cancer (Fisher's exact test, P=0.018). All 4 patients were men with drinking and smoking habits. Among the other 6 women, there was one incidence of small intestine cancer and one of colon cancer. Neither p.R22H nor p.R283Q carriers had GI cancer. DAO p.P103L is reported to be a modifier of amyotrophic lateral sclerosis (ALS) and may potentially be a hypomorphic allele. Thus, it is hypothesized that this rare variant might have affected protection against gastric mucosal damage through H(2)S signaling in the mucosa, which leads to high prevalence of gastric cancer. The role of rare variant DAO p.P103L warrants further investigation in larger cohorts.