Association Of Heparanase Gene(HPSE-1) Single Nucleotide Polymorphisms With Gastric Cancer

ObjectiveGastric cancer is one of the most common malignancies in the world, particularly in Eastern Asian countries such as China, Korea, and Japan. Despite the advance in diagnosis and treatment, the prognosis for advanced gastric cancer is poor, with a 5-year survival rate about 20%-30%. Over the past years, many evidences have clearly demonstrated that multiple genetic alterations are responsible for the development and progression of gastric cancer. Changes of specific genes in gastric cancer play important roles in cell adhesion, signal transduction, cell differentiation, development and metastasis. Better understanding of the molecule mechanism of gastric cancer will profit the diagnosis, treatment and precaution of the disease.Single nucleotide polymorphisms (SNPs) are thought to be the genetic basis of most human diseases, or at least positional markers for our genetic heritage. Recent studies show that low-penetrance disease susceptibility genes, which are relatively common in the population, may confer a much higher attributable risk in the general population than rare mutations in high-penetrance disease susceptibility genes. In the last several years, attention in the human genetics community has increasingly turned from the study of single-gene, Mendelian disorders to the search for DNA sequence variants associated with increased risks for the developed of common, or complex diseases caused by the interaction of hereditary and environmental influences. The great majority of SNPs are not associated with changes in gene structure or function, but a small proportion are believed to be directly responsible for genetic disease. One of the central challenges of modern human genetics is to identify these deleterious SNPs. Studies to investigate the role of SNPs in genetic susceptibility to human diseases will offer the possibility of designing novel targeted therapies in the future.Heparanase specifically cleaves heparan sulfate (HS) side chains of heparan sulfate glycosaminoglycans, the principal polysaccharide component of the basement membrane (BM) and extracellular matrix (ECM). Cleavage of HS disintegrates the structural integrity of the basement membrane and releases HS-bound bioactive angiogenic and growth-promoting mediators such as fibroblast growth factor and vascular endothelial growth factor (VEGF). HS and heparanase have been implicated in diverse processes such as cell proliferation, cell-matrix adhesion, cell-cell adhesion, migration, angiogenesis and wound healing. Heparanase gene overexpression has been associated with advanced stage and poor survival in several cancers.Polymorphisms in the HPSE-1 gene could alter enzyme expression.This study aimed at investigating the potential association between single nucleotide polymorphisms (SNPs) of the HPSE-1 gene, tumor susceptibility, clinicopathological parameters, and survival with gastric cancer among the Han population in northern China.Materials and MethodsUnrelated subjects from Shenyang of China were enrolled for this studies. The trial recruited 155 gastric cancer patients and 204 healthy control subjects. Cases were patients with a histologically confirmed new diagnosis of gastric cancer in the First Affiliated Hospital of China Medical University between 2000 and 2003. Gastric cancer patients were 108 men and 47 women; the median age was 56 years. Gastric cancer patients were grouped according to TNM-classification (UICC), on the basis of the postoperative histopathology evaluation.Controls were randomly selected among the people admitted to the same hospital during the same period. Control subjects were 107 men and 97 women; the median age was 60 years. These control subjects had no history of cancer.All subjects were consent to participate in the study, and allow their blood samples to be analyzed. The polymorphisms were detected by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Statistical analyses were undertaken using the SPSS13.0 Statistical Package and SHESIS Statistical Package.Results1. HPSE-1 gene SNP and tumor susceptibilityThere was an increase in frequency of individuals with a genotype that carried the intron3 (A), exon8 (A), exonl3 (G) haplotype (AAG) in patients with gastric cancer compared with healthy individuals (P=0.0001; OR=7.467; 95% CI:2.274-24.509)2. HPSE-1 gene SNP and clinicopathological parametersSNP rs 11099592 variant genotypes AG/AA were associated with Borrmann's classification (P=0.015; OR=0.182; 95% CI 0.049-0.668) and invasive depth (p=0.020; OR=0.341; 95% CI 0.134-0.866).3. HPSE-1 gene SNP and survivalSNP rs6856901 variant genotypes GC/CC were associated with a better tumor-related survival (P=0.028; OR=0.504; 95%CI:0.273-0.930) compared with GG genotype.Conclusions1. Haplotype (AAG) more likely to have gastric cancer.2 SNP exon8 correlated with superficial invasion.3 SNP exonl3 correlated with better survival.