Zong Yuan, Tanaka Masashi, Muramatsu Masaaki, Arai Tomio
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Mol Clin Oncol. 2021 Mar;14(3):58. doi: 10.3892/mco.2021.2220. Epub 2021 Jan 24.
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 (HS) 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 HS 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.
胃癌在亚洲人群中很常见。胃癌的遗传易感性尚未完全明确。最近的研究表明，D-氨基酸氧化酶（DAO）是一种多功能酶，可通过在啮齿动物胃中产生硫化氢（HS）来保护胃肠道（GI）黏膜。本研究调查了人类DAO基因中的罕见种系变异与胃癌发病率的关系。采用JG-SNP数据库中登记的连续尸检病例（n = 2343；平均年龄80岁），并用外显子珠芯片进行基因分型。有三个非同义罕见变异，即p.R22H、p.P103L和p.R283Q，其次要等位基因频率分别为0.09%、0.21%和0.02%。对这些变异的携带者进行了调查，结果显示，10名携带p.P103L变异的患者中有4人患有胃癌（Fisher精确检验，P = 0.018）。所有4名患者均为有饮酒和吸烟习惯的男性。在其他6名女性中，有1例患小肠癌，1例患结肠癌。携带p.R22H和p.R283Q变异的患者均未患胃肠道癌症。据报道，DAO p.P103L是肌萎缩侧索硬化症（ALS）的一个修饰因子，可能是一个低表达等位基因。因此，推测这种罕见变异可能通过黏膜中的HS信号影响对胃黏膜损伤的保护作用，从而导致胃癌的高发病率。罕见变异DAO p.P103L的作用值得在更大的队列中进一步研究。
