Genetic association of osteopontin (OPN) and its receptor CD44 genes with susceptibility to Chinese gastric cancer patients.

PURPOSE: (1) To investigate associations between single nucleotide polymorphisms (SNPs) in osteopontin (OPN) and its receptor-cluster of differentiation 44 (CD44) genes and gastric cancer susceptibility. (2) To explore the correlation of OPN and CD44 expression of gastric cancer. METHODS: We detected 26 SNPs of the genes in gastric cancer patients from the Chinese Han population by Sequenom technique and performed expression of OPN in combination with CD44 in 243 tissues samples of the cases by tissue microarray and immunohistochemistry (IHC). RESULTS: We found that the minor alleles of OPN rs4754C>T and OPN rs9138C>A remained strongly associated with decreased gastric cancer risk (P = 1.53 × 10(-4), odds ratio (OR) 0.642, 95 % confidence interval (CI) 0.511-0.808 and P = 1.59 × 10(-4), OR 0.642, 95 %CI 0.510-0.809). OPN variant rs1126772A>G and CD44 variant rs353639A>C significantly contributed to elevated risk of gastric cancer (P = 0.042, OR 1.279, 95 % CI 1.008-1.622 and P = 0.047, OR 1.334, 95 % CI 1.003-1.772). Haplotypes of OPN and CD44 variants significantly influenced risk of gastric cancer. Clinical data indicated that rs4754 and rs9138 of OPN were significantly associated with smoking (P = 0.029, OR 0.343, 95 % CI 0.127-0.926 and P = 0.029, OR 0.343, 95 %CI 0.127-0.926) and OPN rs1126772 revealed associations with tumor-node-metastasis (TNM) stage (P = 0.025, OR 1.765, 95 % CI 1.073-2.905) and tumor differentiation (P = 0.031, OR 1.722, 95 % CI 1.049-2.825). OPN expression was observed in 133 of the 243 cases (54.7 %) by IHC and was correlated with serosa invasion (P = 0.013), TNM stage (P = 0.003) and lymph node metastasis (P = 0.002). CD44 expression was found in 92 of the 243 cases (37.9 %) and was associated with tumor size (P = 0.005) and lymph node metastasis (P = 0.023), respectively. The OPN expression displayed a positive association with CD44 (P = 0.01, r s = 0.164). CONCLUSIONS: We found that the polymorphisms rs4754, rs9138 and rs1126772 of OPN gene and rs353639 of CD44 gene were significantly associated with gastric cancer. Our IHC data indicated that interaction of OPN and CD44 protein would promote progression and metastasis of gastric cancer.

Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population.

The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing steroidogenic acute regulatory-related lipid transfer domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, haplotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P=0.043, odds ratio [OR]=0.805, 95% confidence intervals [95% CI]=0.643-0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P=0.021, OR=2.882, 95% CI=1.173-7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). The expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P=0.004), alcohol drinking (P<0.001), tumor location (P=0.007), histological type (P=0.005) and differentiation (P=0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population.

Genetic analysis of ADIPOQ variants and gastric cancer risk: a hospital-based case-control study in China.

Single-nucleotide polymorphisms (SNPs) of adiponectin (ADIPOQ), adiponectin receptor 1 (ADIPOR1) and ADIPOR2 genes contribute to the risk and progression of cancers. Here, we investigated the associations between variants of these three genes and the risk of gastric cancer. We genotyped six ADIPOQ SNPs, nine ADIPOR1 SNPs and six ADIPOR2 SNPs using the Sequenom technique in a hospital-based case-control study of patients with gastric cancer and cancer-free controls in the Chinese Han population. We found associations of certain variants with location of gastric cancer. Rs16861205 with the minor allele A in ADIPOQ, rs10773989 with the minor allele C and rs1044471 with the minor allele T in ADIPOR2 presented significant associations with a decreased risk of cardia cancer (P = 0.024, OR 0.605, 95 % CI 0.390-0.938; P = 0.015, OR 0.699, 95 % CI 0.522-0.935; and P = 0.022, OR = 0.703, 95 % CI 0.519-0.951, respectively). ADIPOQ rs16861205 with minor allele A displayed an association with an increased risk of body cancer (P = 0.010, OR 1.821, 95 % CI 1.148-2.890). Further stratified analysis of the patients indicated that there were significant correlations for rs1342387A/G (P = 0.027) and rs16861205A/G (P = 0.000) with tumor location; rs16850799A/G (P = 0.004) and rs2058033C/A (P = 0.003) with invasion depth; rs16850799A/G (P = 0.019) with the tumor-node-metastasis stage; rs16850799A/G (P = 0.016), rs1501299A/C (P = 0.005) and rs1063538C/T (P = 0.017) with alcohol consumption; rs11612414A/G (P = 0.040) and rs12733285T/C (P = 0.005) with salted food; rs1063538C/T (P = 0.043) with family history of gastric cancer; and rs11612414A/G (P = 0.029) with gender. Adiponectin expression significantly correlated with gender (P = 0.014), alcohol consumption (P = 0.037), family history (P = 0.019) and invasion depth of primary tumor (P = 0.024). Our data suggested that variants of ADIPOQ may be genetic markers conferring susceptibility to gastric cancer subtypes. These findings need to be validated in a larger panel of samples from distinct populations.

E-selectin rs5361 and FCGR2A rs1801274 variants were associated with increased risk of gastric cancer in a Chinese population.

Host immune responses are critical steps for carcinogenesis. Single nucleotide polymorphisms (SNPs) in immunoregulatory genes may influence gastric cancer risk. We performed a genotyping analysis for immunoregulatory genes in 311 gastric cancer cases and 425 controls from a Chinese population. We found that there were significant differences of E-selectin variant rs5361 (A>C) and FCGR2A variant rs1801274 (T>C) between cases and controls (P = 0.022 and P = 0.0001, respectively). Logistic regression analysis indicated that genotype of E-selectin rs5361AC increased the risk of gastric cancer significantly (P = 0.026, adjusted Odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.13-7.12). C allele of E-selectin rs5361 showed a significant increased frequency in cases (P = 0.023). However, the E-selectin variant did not affect the protein expression. E-selectin protein was observed not only in tumor interstitial vascular endothelial cells, but also in gastric cancer cells at primary and metastatic sites. The protein was associated with clinicopathological characteristics of gastric cancer, such as age (P = 0.008), tumor size (P = 0.027), differentiation (P = 0.000), and tumor-node-metastasis (TNM) stage (P = 0.006). CT and CC + CT genotypes of FCGR2A variant rs1801274 increased gastric cancer risk (P = 0.000, adjusted OR = 1.92, 95%CI = 1.36-2.72; P = 0.003, adjusted OR = 1.68, 95%CI = 1.20-2.35, respectively). Interleukin-4 receptor (IL-4R) variant rs2107356 presented negative correlations to E-selectin variant rs5361 and FCGR2A variant rs1801274 (P = 0.035 and P = 0.023) in conferring susceptibility to gastric cancer. We concluded E-selectin variant rs5361 and FCGR2A variant rs1801274 were significantly associated with gastric cancer risk. Expression of E-selectin protein would promote progression of gastric cancer.