STAT3 polymorphism and Helicobacter pylori CagA strains with higher number of EPIYA-C segments independently increase the risk of gastric cancer

Abstract

BackgroundBecause to date there is no available study on STAT3 polymorphism and gastric cancer in Western populations and taking into account that Helicobacter pylori CagA EPIYA-C segment deregulates SHP-2/ERK-JAK/STAT3 pathways, we evaluated whether the two variables are independently associated with gastric cancer.MethodsWe included 1048 subjects: H. pylori-positive patients with gastric carcinoma (n = 232) and with gastritis (n = 275) and 541 blood donors. Data were analyzed using logistic regression model.ResultsThe rs744166 polymorphic G allele (p = 0.01; OR = 1.76; 95 % CI = 1.44-2.70), and CagA-positive (OR = 12.80; 95 % CI = 5.58-19.86) status were independently associated with gastric cancer in comparison with blood donors. The rs744166 polymorphism (p = 0.001; OR = 1.64; 95 % CI = 1.16-2.31) and infection with H. pylori CagA-positive strains possessing higher number of EPIYA-C segments (p = 0.001; OR = 2.28; 95 % CI = 1.41-3.68) were independently associated with gastric cancer in comparison with gastritis. The association was stronger when host and bacterium genotypes were combined (p < 0.001; OR = 3.01; 95 % CI = 2.29-3.98). When stimulated with LPS (lipopolysaccharide) or Pam3Cys, peripheral mononuclear cells of healthy carriers of the rs744166 GG and AG genotypes expressed higher levels of STAT3 mRNA than those carrying AA genotype (p = 0.04 for both). The nuclear expression of phosphorylated p-STAT3 protein was significantly higher in the antral gastric tissue of carriers of rs744166 GG genotype than in carriers of AG and AA genotypes.ConclusionsOur study provides evidence that STAT3 rs744166 G allele and infection with CagA-positive H. pylori with higher number of EPIYA-C segments are independent risk factors for gastric cancer. The odds ratio of having gastric cancer was greater when bacterium and host high risk genotypes were combined.

Associations of potentially functional variants in IL-6, JAKs and STAT3 with gastric cancer risk in an eastern Chinese population

“…The rs4796793 SNP, together with rs744166 that is in high LD with rs4796793 (r 2 >0.8), is the most widely studied STAT3 SNP in various cancers. However, two studies reported some opposite results in association with GCa risk; one Chinese study found that rs744166 SNP might be associated with a decreased risk of GCa in an Northeast Chinese population with 209 GCa patients and 294 cancer-free controls, while a Brazilian study showed that rs744166 SNP was associated with an increased GCa risk in a South American population with 232 GCa cases and 541 cancer-free controls [ 23 , 36 ]. The inconsistent results of three studies (including the present study) may be explained by the differences in sample sizes and study populations with different exposures, such as age, smoking, and alcohol use, which is also consistent with the results of our stratified analysis, in which the risk varied among the subgroups whose samples were further reduced.…”

“…The study population consisted of 1,130 unrelated Han Chinese patients with newly diagnosed and histopathologically confirmed primary gastric adenocarcinoma from an ongoing molecular epidemiology study [ 23 , 24 ] at Fudan University Shanghai Cancer Center (FUSCC) between 2009 and 2011. All patients came from eastern China, including Shanghai, Jiangsu, Zhejiang, Anhui and the surrounding regions.…”

“…In fact, studies have reported associations between single nucleotide polymorphisms (SNPs) of IL-6 and risk of GCa, but these studies had a relatively small sample size, with only one larger study of 439 cases and 1138 controls conducted in European descendants [ 18 – 22 ]. Other studies have reported associations of some SNPs of STAT3 and JAK2 with risk of GCa, but all with less than 300 GCa patients [ 23 ].…”

Role of polymorphisms in genes that encode cytokines and Helicobacter pylori virulence factors in gastric carcinogenesis

“…Infections by strains containing CagA are more capable to induce carcinogenic processes, mainly those with EPIYA-D or more than one EPIYA-C segment[ 57 ]. Various cag PAI genes are involved in the codification of elements of a pilus structure named type IV secretion system (TFSS), which has the function of transporting CagA from bacterium to the cytoplasm of the cells from gastric epithelium[ 58 ].…”

Association of Single Nucleotide Polymorphisms in <i>STAT3</i>, <i>ABCB1</i>, and <i>ABCG2</i> with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patients

“…1,9,10) STAT3 regulates the expression of several genes involved in a variety of cellular responses including proliferation, differentiation, apoptosis, and wound healing. 11,12) Furthermore, it was reported that activating STAT3 can promote oral mucosal wound healing, 13) STAT3 may play a key role for regulating homeostasis of oral mucosa.…”