Study Of Chromosome Abnormalities And Expression Of Angiogenesis Regulation Genes Of HCC Patients

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This particular type of carcinoma has poor survival rate and high post operation recurrence rate. Early diagnosis of HCC patients is challenge, which limits treatment options and resulting in poor prognosis and outcome. Identification of gene(s) responsible for HCC is necessary for both prediction of clinical outcome and biomarker for therapy.However, carcinogenesis is a multi-step process and progression is caused by the accumulation of genetic aberrations. Cancer cells often contain large numbers of severe copy number(CN) alterations of chromosomal segments, called chromosomal abnormalities, that accelerate cancer progression. Abnormalities related to oncogenes and tumor suppressor genes have been reported recently. There are regional variations in the clinical presentation and the natural history of HCC.The angiogenesis of new blood vessels, is the essential factor for malignant tumor growth and spreading tumor cells to the body. Some studies have confirmed the association of microvessel density(MVD) with tumor staging. Angiogenesis is regulated in large part by the balance of various angiogenic stimulators, and a diverse group of inhibitors of angiogenesis. VEGF is one of the most important angiogenic stimulators. A new inhibitor, called vasohibin-1, is coded by gene VASH1and selectively induced in endothelial cells by proangiogenic stimulatory growth factors such as VEGF, it appears to operate as an intrinsic and highly specific feedback inhibitor of VEGF and inhibited the process of angiogenesis. HCC is a hypervascular solid tumor with a high tendency towards vascular invasion. The angiogenesis process related factors HIF-1A, VHL, VASH1, VEGF are attractive for HCC targeted therapy.My experiment was to study chromosome abnormalities of local HCC patients and the association of expression of angiogenesis related genes with the clinicopathological characteristics and prognosis. Identify biomarkers for prediction of metastasis and prognosis, and provides a new idea for further clinical service.Methods we used are as follows: 1. Analysis whole genome level of HCC cases treated by surgical operation in our hospital, using oligoarray CGH, to reveal possible common chromosomal regions that may harbor genes responsible for HCC development, progression or outcome.2. Study the expression of genes of angiogenic stimulators and inhibitors:VEGF, HIF1A, VHL, VASH1and CD34(marker of MVD) by tissue array and immunohistochemical technique.3Use statistical methods to analysis the relationship between gene expression and clinical characteristic and prognosis.The major results are as follows:1. Most of the DNA arms have abnormalities. Most of the cases have abnormalities. And differentiation, vascular invasion, survival of the postresection are associated with DNA arms abnormalities.2. Chromosome segments where angiogenesis related genes HIF1A and VASH1located on has a higher percentage of heterozygosity. But expression of the two genes has no obvious difference between tumor tissues and adjacent tissues, and has no relationship to clinicopathological features and outcomes which means more complicated mechanism in tumor initiation and progression.3. The expression of VHL in adjacent tissues is stronger than tumor tissues, and the expression of VEGF in tumor tissues is stronger than adjacent tissues.4. The expression of HBsAg/HBcAg was higher in adjacent tissues than that of HCC cancer tissues with chronic HBV infection. The expression of HBsAg/HBcAg was not correlated with the postoperative survival.5. The serum level of AFP had no correlation with postoperative survival.6. Tumor size and HCV infection were the independent influencing factors of prognosis of HCC patients.Together, we got these conclusions:1. Differentiation, vascular invasion, postoperative survival are associated with chromosome aberrations of HCC.2. Chromosome segments where angiogenesis related genes HIF1A and VASH1located on has a higher percentage of heterozygosity. But expression of the two genes has no obvious difference between tumor tissues and adjacent tissues, and has no relationship to clinicopathological features and outcomes.3. VHL and VEGF may be regarded as biomarkers in local HCC biotherapy. 4. Tumor size and HCV infection were the independent influencing factors of prognosis of HCC patients, but HBV infection and level of serum AFP had no correlation with postoperative survival.The innovation pointIn this study, we integratively analyzed HCC patients’s Chromosome abnormalities and expression of angiogenesis process related factors HIF1A, VHL, VASH1, VEGF by385K aCGH and tissue array, and analyzed the relationship between the genes and clinical characteristic and prognosis. We can draw the conclusion that VHL and VEGF may be regarded as biomarkers in local HCC biotherapy...