CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma

Abstract

Infection with Helicobacter pylori (H. pylori) increases stomach cancer risk. Helicobacter pylori strains with the cag pathogenicity island (PAI) induce more severe inflammation in the gastric epithelium and are more strongly associated with stomach cancer risk than strains lacking the PAI. We examined whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains. DNA from 105 microdissected tumor specimens was analyzed for mutation in exons 5-8 of the p53 gene by polymerase chain reaction-based single-strand conformation polymorphism followed by direct DNA sequencing. Enzyme-linked immunosorbent assays for IgG antibodies against H. pylori and CagA were performed on sera collected 2-31 years prior to cancer diagnosis. Tumors from CagA(+) subjects were significantly more likely to have p53 mutations than tumors from CagA(-) subjects (including H. pylori- and H. pylori(+)/CagA(-)): odds ratio = 3.72; 95% confidence interval, 1.06-13.07 after adjustment for histologic type and anatomic subsite of tumor and age at diagnosis and sex of subjects. Mutations were predominantly insertions and deletions (43%) as well as transition mutations at CpG dinucleotides (33%). The data suggest that CagA(+) H. pylori infection, when compared with CagA(-) infection or the absence of H. pylori infection, is associated with a higher prevalence of p53 mutation in gastric adenocarcinoma.

H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: Correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression

“…Kodama et al [43] have suggested an accumulation of wild-type p53, especially in the H pylori infected mucosa probably due to the H pylori-induced DNA damage. The present study shows the highest frequency of p53 mutation in the groups with H pylori infection, especially among the cagA+ cases, corroborating previous studies [16,3,4] . The high percentage of p53 mutation in EBV-associated and EBV-negative gastric carcinomas was observed in our study which was also demonstrated in other studies, demonstrating that the p53 mutation is a relevant alteration in gastric carcinogenesis independent of the infection [15,16,43] .…”

“…The frequency of H pylori infection (94.4%) was higher than previous studies, where it ranged from 34.1% to 92%. These differences can be due to: (a) the sensitivity of the screening technique, since most previous studies used serology, rapid urease test and/or histological evaluation; (b) and the fact that these studies were performed in different world regions and it is known that the H pylori infection is more frequent in developing countries [8,16,[22][23][24] . On the other hand, EBV was detected in 8.45% of our cases.…”

“…Some of these, like c-Myc, p53 and the apoptotic family members such as Bcl-2 and Bax, deserve attention for playing a key function in the cell proliferation and cell fate, besides they already have shown involvement in the tumorigenesis process in a variety of tumors, including gastric cancer [11][12][13] . Although the proteins mentioned above have different levels of alteration in gastric carcinoma, the association with H pylori or EBV is controversial [14][15][16] . Additionally, there is just one paper related H pylori and EBV infection with concomitant analysis, in gastric carcinomas, in which, proteins involved in cell cycle and apoptosis process were also evaluated [10] .…”

Inflammation, atrophy, and gastric cancer

“…Indeed, although diffuse-type gastric cancer is strongly associated with infection with H. pylori, it is equally associated with strains containing the cag PAI and those lacking it (42). Individuals infected with H. pylori strains containing the cag PAI have also been shown to have an increased likelihood of having mutations in the gene encoding p53 (44). This correlates with the observation that p53 +/-mice transgenic for the lacI gene (which enables researchers to measure the rate of genetic mutations) that are chronically infected with Helicobacter felis have a cumulative increase in gastric tissue mutations and ostensibly an increased cancer risk (45).…”

Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples

“…(13)(14)(15)(16)(17)(18)(19) In terms of epigenetic alterations, reduced expression of acetylated histone H4 or DNA methylation of CDH1 and RAR-β have been shown to be correlated with tumor invasiveness and the tumor metastasizing potential. (20,21) On the other hand, the recent introduction of the microarray technology has enabled significant genes to be identified almost throughout the genome using a hypothesis-free approach.…”