Interplay between Helicobacter pylori and host gene polymorphisms in inducing oxidative DNA damage in the gastric mucosa

Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132, Genoa, Italy.
Carcinogenesis (Impact Factor: 5.33). 05/2007; 28(4):892-8. DOI: 10.1093/carcin/bgl208
Source: PubMed


Infection by Helicobacter pylori is the most important risk factor for gastric cancer. However, only a small fraction of colonized individuals, representing at least half of the world's population, develop this malignancy. In order to shed light on host-microbial interactions, gastric mucosa biopsies were collected from 119 patients suffering from dyspeptic symptoms. 8-Hydroxy-2'-deoxyguanosine (8-oxo-dG) levels in the gastric mucosa were increased in carriers of H.pylori, detected either by cultural method or by polymerase chain reaction, and were further increased in subjects infected with strains positive for the cagA gene, encoding the cytotoxin-associated protein, cagA. Oxidative DNA damage was more pronounced in males, in older subjects, and in H.pylori-positive subjects suffering from gastric dysplasia. Moreover, 8-oxo-dG levels were significantly higher in a small subset of subjects having a homozygous variant allele of the 8-oxoguanosine-glycosylase 1 (OGG1) gene, encoding the enzyme removing 8-oxo-dG from DNA. Conversely, they were not significantly elevated in glutathione S-transferase M1 (GSTM1)-null subjects. Thus, both bacterial and host gene polymorphisms affect oxidative stress and DNA damage, which is believed to represent a key mechanism in the pathogenesis of gastric cancer. The interplay between bacterial and host gene polymorphisms may explain why gastric cancer only occurs in a small fraction of H.pylori-infected individuals.

Download full-text


Available from: Antonio M Scanu,
  • Source
    • "pylori) infection is a major risk factor [4] [5]. Increasing evidence has shown that cagA protein, an important H. pylori-produced virulent factor for gastric mucosa injury, could induce many kinds of DNA damage including DNA base damage, DNA double-strand break (DSBs), and oxidative damage [5] [6] [7] [8] [9] [10]. Among these DNA damages, DSBs are the most detrimental form [11] [12], because they may lead to both chromosomal breakage and rearrangement and ultimately lead to tumorigenesis of cancers such as GAA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The X-ray repair cross-complementing group 7 (XRCC7) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. To determine whether XRCC7 rs#7003908 polymorphism (XRCC7P) is associated with Helicobacter pylori (H. pylori) infection-related gastric antrum adenocarcinoma (GAA) risk, we conducted a hospital-based case-control study, including 642 patients with pathologically confirmed GAA and 927 individually matched controls without any evidence of tumours or precancerous lesions, among Guangxi population. Increased risks of GAA were observed for individuals with cagA positive (odds ratio (OR) 6.38; 95% confidence interval (CI) 5.03-8.09). We also found that these individuals with the genotypes of XRCC7 rs#7003908 G alleles (XRCC7-TG or -GG) featured increasing risk of GAA (ORs 2.80 and 5.13, resp.), compared with the homozygote of XRCC7 rs#7003908 T alleles (XRCC7-TT). GAA risk, moreover, did appear to differ more significantly among individuals featuring cagA-positive status, whose adjusted ORs (95% CIs) were 15.74 (10.89-22.77) for XRCC7-TG and 38.49 (22.82-64.93) for XRCC7-GG, respectively. Additionally, this polymorphism multiplicatively interacted with XRCC3 codon 241 polymorphism with respect to HCC risk (ORinteraction = 1.49). These results suggest that XRCC7P may be associated with the risk of Guangxiese GAA related to cagA.
    International Journal of Genomics 11/2013; 2013:124612. DOI:10.1155/2013/124612 · 0.95 Impact Factor
  • Source
    • "Large-scale studies have shown a correlation between Helicobacter pylori seroprevalence and the incidence and mortality rate of GA (Ferreccio et al. 2007 ; Groves et al. 2002). The infection results in an imbalance between the production of reactive oxygen species (ROS) and the body's ability to remove the reactive intermediates or repair the resulting damage (Handa et al. 2007 ; Izzotti et al. 2007). Toxic effects are caused through the production of peroxides and free radicals that damage various biomolecules in humans, such as protein, lipids, DNA and RNA (Kawanishi et al. 2006 ; Rainis et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent data from several studies suggest that oxidative stress is involved in the biochemical mechanisms that underlie neuropsychiatric disorders. The present study was designed to investigate oxidative stress status in depressive patients with gastric adenocarcinoma (GA) at TNM stage III. Oxidative stress, depression and expression of specific genes were monitored during a pretreatment period. Serum total antioxidant capacity, catalase, superoxide dismutase concentrations, and antisuperoxide anion capacity (A-ASC) were significantly decreased in depressive patients compared to control subjects, whereas serum malondialdehyde (MDA) levels were significantly increased. Importantly, the formation of 8-hydroxy-deoxyguanosine (8-OHdG) accumulated. Furthermore, SYBR Green real-time PCR revealed that the expression levels of human oxoguanine glycosylase 1 and APEX nuclease 1 (APEX1) were increased in depressive patients. Pearson correlation analysis revealed that depression was positively correlated with SAS, SCL-90, MDA, 8-OHdG and APEX1, but negatively correlated with A-ASC. Thus, this study confirms oxidative imbalance in depressive patients with GA, and oxidative stress may play a role in the onset and exacerbation of depression.
    The International Journal of Neuropsychopharmacology 04/2009; 12(8):1089-96. DOI:10.1017/S1461145709000091 · 4.01 Impact Factor
  • Source
    • "For some chronic infections, tissues may remain infected for decades, encountering multiple rounds of inflammation and necrosis/ wounding followed by healing. Hence, the cancer risk would be amplified at each cycle (Ames et al., 1995; Mostafa et al., 1999; Friedberg et al., 2006; Lu et al., 2006; Izzotti et al., 2007). The connection between chronic infection, resulting in persistent inflammation, and cancer has been clearly documented for a few infectious diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An accumulating body of research indicates there is an increased cancer risk associated with chronic infections. The genus Mycobacterium contains a number of species, including M. tuberculosis, which mount chronic infections and have been implicated in higher cancer risk. Several non-tuberculosis mycobacterial species, including M. marinum, are known to cause chronic infections in fish and like human tuberculosis, often go undetected. The elevated carcinogenic potential for fish colonies infected with Mycobacterium spp. could have far reaching implications because fish models are widely used to study human diseases. Japanese medaka (Oryzias latipes) is an established laboratory fish model for toxicology, mutagenesis, and carcinogenesis; and produces a chronic tuberculosis-like disease when infected by M. marinum. We examined the role that chronic mycobacterial infections play in cancer risk for medaka. Experimental M. marinum infections of medaka alone did not increase the mutational loads or proliferative lesion incidence in all tissues examined. However, we showed that chronic M. marinum infections increased hepatocellular proliferative lesions in fish also exposed to low doses of the mutagen benzo[a]pyrene. These results indicate that chronic mycobacterial infections of medaka are acting as tumor promoters and thereby suggest increased human risks for cancer promotion in human populations burdened with chronic tuberculosis infections.
    Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 03/2009; 149(2-149):152-160. DOI:10.1016/j.cbpc.2008.09.011 · 2.30 Impact Factor
Show more