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

Zong,Yuan; Tanaka,Masashi; Muramatsu,Masaaki; Arai,Tomio

doi:10.3892/mco.2021.2220

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

Authors:
- Yuan Zong
- Masashi Tanaka
- Masaaki Muramatsu
- Tomio Arai
View Affiliations

Affiliations: 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
Published online on: January 24, 2021 https://doi.org/10.3892/mco.2021.2220
Article Number: 58
Copyright: © Zong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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 (H₂S) 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 H2S 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.

View Figures

View References

1	Lott PC and Carvajal-Carmona LG: Resolving gastric cancer aetiology: An update in genetic predisposition. Lancet Gastroenterol Hepatol. 3:874–883. 2018.PubMed/NCBI View Article : Google Scholar
2	Rahman R, Asombang AW and Ibdah JA: Characteristics of gastric cancer in Asia. World J Gastroenterol. 20:4483–4490. 2014.PubMed/NCBI View Article : Google Scholar
3	Yusefi AR, Bagheri Lankarani K, Bastani P, Radinmanesh M and Kavosi Z: Risk factors for gastric cancer: A systematic review. Asian Pac J Cancer Prev. 19:591–603. 2018.PubMed/NCBI View Article : Google Scholar
4	Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, et al: Pathogenic germline variants in 10,389 adult cancers. Cell. 173:355–370.e14. 2018.PubMed/NCBI View Article : Google Scholar
5	Kimura H: Signalling by hydrogen sulfide and polysulfides via protein S-sulfuration. Br J Pharmacol. 177:720–733. 2020.PubMed/NCBI View Article : Google Scholar
6	Shen F, Zhao CS, Shen MF, Wang Z and Chen G: The role of hydrogen sulfide in gastric mucosal damage. Med Gas Res. 9:88–92. 2019.PubMed/NCBI View Article : Google Scholar
7	Shibuya N, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, Fukui K, Nagahara N and Kimura H: A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun. 4(1366)2013.PubMed/NCBI View Article : Google Scholar
8	Tang S, Huang D, An N, Chen D and Zhao D: A novel pathway for the production of H2 S by DAO in rat jejunum. Neurogastroenterol Motil. 28:687–692. 2016.PubMed/NCBI View Article : Google Scholar
9	Sasabe J, Miyoshi Y, Rakoff-Nahoum S, Zhang T, Mita M, Davis BM, Hamase K and Waldor MK: Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol. 1(16125)2016.PubMed/NCBI View Article : Google Scholar
10	Souza LK, Araújo TS, Sousa NA, Sousa FB, Nogueira KM, Nicolau LA and Medeiros JV: Evidence that d-cysteine protects mice from gastric damage via hydrogen sulfide produced by d-amino acid oxidase. Nitric Oxide. 64:1–6. 2017.PubMed/NCBI View Article : Google Scholar
11	Sawabe M, Arai T, Kasahara I, Esaki Y, Nakahara K, Hosoi T, Orimo H, Takubo K, Murayama S and Tanaka N: Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP). Mech Ageing Dev. 125:547–552. 2004.PubMed/NCBI View Article : Google Scholar
12	Oda K, Tanaka N, Arai T, Araki J, Song Y, Zhang L, Kuchiba A, Hosoi T, Shirasawa T, Muramatsu M and Sawabe M: Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: A pathological study of 1503 consecutive autopsy cases. Hum Mol Genet. 16:592–599. 2007.PubMed/NCBI View Article : Google Scholar
13	Kim EJ, Kim YE, Jang JH, Cho EH, Na DL, Seo SW, Jung NY, Jeong JH, Kwon JC, Park KH, et al: Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia. Neurobiol Aging. 72:186.e1–186.e7. 2018.PubMed/NCBI View Article : Google Scholar
14	Zhang H, Cai W, Chen S, Liang J, Wang Z, Ren Y, Liu W, Zhang X, Sun Z and Huang X: Screening for possible oligogenic pathogenesis in Chinese sporadic ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 19:419–425. 2018.PubMed/NCBI View Article : Google Scholar
15	Barber IS, Braae A, Clement N, Patel T, Guetta-Baranes T, Brookes K, Medway C, Chappell S, Guerreiro R, Bras J, et al: Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array. Neurobiol Aging. 49:215.e1–215.e8. 2017.PubMed/NCBI View Article : Google Scholar
16	Pang SY, Hsu JS, Teo KC, Li Y, Kung MHW, Cheah KSE, Chan D, Cheung KMC, Li M, Sham PC and Ho SL: Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. Neurobiol Aging. 58:238.e9–238.e15. 2017.PubMed/NCBI View Article : Google Scholar
17	Pollegioni L, Sacchi S and Murtas G: Human D-Amino acid oxidase: Structure, function, and regulation. Front Mol Biosci. 5(107)2018.PubMed/NCBI View Article : Google Scholar
18	Sacchi S, Cappelletti P and Murtas G: Biochemical properties of human D-amino acid oxidase variants and their potential significance in pathologies. Front Mol Biosci. 5(55)2018.PubMed/NCBI View Article : Google Scholar
19	Ang TL and Fock KM: Clinical epidemiology of gastric cancer. Singapore Med J. 55:621–628. 2014.PubMed/NCBI View Article : Google Scholar
20	Nozaki I, Kato-Motozaki Y, Ikeda T, Tagami A, Takahashi K, Ishida C and Komai K: Clinical features in association with neurodegenerative diseases and malignancies. Eur Neurol. 71:99–105. 2014.PubMed/NCBI View Article : Google Scholar