| Gastric cancer is the most common digestive tumor in the world, there are1.4million cases of cancer of the Gastric cancer and the Gastric esophagus cancer was diagnosed each year,1.1million patients died of Gastric cancer every year,it is the second malignant tumor has serious harm to to people's life safety and health. Most patients are diagnosed at an advanced (i.e., unresectable) stage, or already have metastatic disease. Although the perioperative and postoperative radiation and chemotherapy can improve the patient's survival, but advanced gastric cancer survival rates are still very low.Incidence of gastric cancer is a multi-part, multi-factors in the pathophysiological process of development, and the environment, diet, H. pylori infection is closely related to, but also the activation of oncogenes, tumor suppressor genes are suppressed, growth factors involved in so are closely related, but its precise mechanism were not been understood. Therefore, the relationship between changes in gene function studies with gastric cancer progression and metastasis of malignant characteristics is important, it useful to reveal the precise molecular mechanisms of the development and discovery of new biomarkers and clinical screening for early gastric cancer, especially in the design of effective therapies is targeted at the biological treatment of abnormal genes and prognosis.HER genes (human epidermal growth receptor2gene), also known as ERBB2or HER2/neu gene. Shih et al found this proto-oncogenes in murine neuroblastoma in1981, HER2is usually high expression in the human fetus, low levels expression in the organization of adult. HER-2gene is located on human chromosome17q21, is belong to human epidermal growth factor receptor (epidermal growth factor receptor, EGFR) family members. EGFR family consists of four members, namely HER-1/EGFR, HER-2/neu, HER-3and HER-4, have a similar molecular structure. Different ligands binding to the extracellular ligand-binding region, will cause a series of signal transduction cascade waterfall, thus affecting the structure of biological cells. Including cell proliferation, apoptosis, adhesion, migration and differentiation.HER-2encoding to185000Da molecular weight single-chain transmembrane glycoprotein, p185, including the intracellular, transmembrane and extracellular regions, the intracellular domain with tyrosine kinase (protein tyrosine kinase, PTK) activity. When combined with growth factors HER1, HER3or HER4, the conformational change in the extracellular region of the protein, and with the HER-2receptor molecules form a heterodimer that intracellular PTK activity is significantly increased. Since HER-2itself has several tyrosine residue (Tyr) phosphorylation sites, PTK substrate identifiable autophosphorylation sites, and in particular the role of signaling proteins induced cell proliferation, differentiation and anti-apoptosis, thereby induce tumorigenesis. Intracellular HER-2gene amplification will cause over-expression of its protein product p185, HER-2receptor to increase the number of heterologous dimers, causing an increase in intracellular PTK activity of tyrosine autophosphorylation, activation multiple signal transduction pathways, so that the cells proliferate, inhibiting apoptosis, promote the development of malignant cells.Since HER-2gene is located on the cell surface receptor, antibody can bind it easily, thus suitable as a target for anti-tumor immunotherapy. Trastuzumab (Herceptin) is a HER2monoclonal antibody targeted therapy of breast cancer that blocks the activation of the extracellular domain of HER2, cause antibody-dependent induction of cancer cell cytotoxicity (antibody-dependent cytotoxicity, ADCC).In the early and advanced (metastatic) breast cancer in both shows better effect. Research shows that in HER2-positive breast cancer women, Herceptin therapy or in combination with chemotherapy use after standard chemotherapy, may improve chemotherapy response rates, disease-free survival and overall survival. Since1998, Herceptin has been used to treat more than450,000HER2-positive breast cancer patients in worldwide.Success of Herceptin in HER2-positive breast cancer treatment, attract researchers apply it in therapy other HER-2-positive tumors, including gastric cancer, including treatment. ToGA (Trastuzumab for Gastric Cancer) clinical trials confirmed Herceptin plus chemotherapy can effectively improve the average survival of HER2-positive Gastric cancer or Gastric esophageal cancer, and HER2expression levels are associated with the effect of treatment. Accurately determine HER-2status is essential to select the appropriate targeted Herceptin patients. Detection of HER-2status include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH). Immunohistochemical widely because of the lower costs, and fluorescence in situ hybridization is considered gold standard of HER-2status Analyzing. Many cancers have been found to exhibit marked heterogeneity in histopathology as well as molecular and genetic expression. With the growing focus on predictive and prognostic biomarkers, considerations of heterogeneity are becoming increasingly important to current research and clinical practice. Tumor heterogeneity can be intratumoral.occurring within a single tumor, and intertumoral, occurring between tumor sites and between tumors of the same type.Heterogeneity also encompasses differential expression of a single biomarker that may occur due to histological differences between different tissue types. Study also found that tumor heterogeneity arise in tumor antigen, immune, hormone receptors, metabolic, growth rate. Tumor heterogeneity may cause Chemosensitivity difference in tumors. Becaued there may be different genotype or subtype cells in one type tumor, therefore these different cells may exhibit different treatment sensitivity and different prognosis.Gastric cancer is considered to be a highly heterogeneous tumors, Influence of tumor heterogeneity on HER-2status interpretation, and the impact of targeted therapy Herceptin is not yet conclusive. In this study, we using immunohistochemistry and fluorescence in situ hybridization methods to assess HER-2status in gastric cancer, furthermore, potentially contribute of tumor heterogeneity on assessment of HER2status were further studied. Part1:Comparison of HER2Status by Fluorescence in Situ Hybridization and Immunohistochemistry in Gastric Cancer AbstractAim of the study:To investigate the differences and relevance and to evaluate the clinical significance of fluorescence in situ hybridization and immunohistochemistry in detecting HER2in gastric cancer tissues.MethodThe expressions of HER2protein and the amplification of the HER2gene in118gastric cancer tissues were detected by fluorescence in situ hybridization and immunohistochemistry, respectively.ResultsUsing IHC, our results were0in40cases (33.9%),1+ in33cases (14%),2+ in16cases (13.6%), and3+ in29cases (25.6%), respectively. Using the FISH test,38of118cases (32.2%) were judged as positive results. The concordance rate between the results of IHC and FISH in all cases was85.6% [95% confidence interval (CI):79.3-91.9%]. In the73cases that the HER2protein was negative (0and1+) according to IHC,68cases did not show amplification with FISH and its concordance rate was93.1%. In the45cases that HER2protein was positive (2+ and3+) according to IHC,33cases showed amplification with FISH and its concordance rate was73.3%. We found no association between HER2gene amplification status and age, gender, T-stage, N-stage, M-stage, or pathology stage.ConclusionIHC cannot predict HER2gene amplification accurately. FISH test should be executed in IHC2+cases. Part2:Study of Her-2Intratumoral heterogeneity in gastriccancer status and impact of heterogeneity on Her-2status interpretationAim of the study:To clarify intratumoral heterogeneity of HER2expression and its potential clinical impact on assessment of HER2status. Methodwe analyzed148endoscopic biopsy specimens and117excisional tumor specimens collected from148patients with primary gastric cancer. Specifically, we assessed HER2protein overexpression and gene amplification using,respectively, immunohistoche-mistry (IHC) and fluorescence in situ hybridization (FISH). ResultsThere were28IHC-positive cases and25FISH-positive cases among these148patients.Heterogeneous HER2protein expression was demonstrated in23of29(79.3%) IHC-positive cases, while gene expression heterogeneity was found in11of25(44.0%) FISH positive cases. Intratumoral heterogeneity was the main reason of discordant results between IHC and FISH or between endoscopic biopsy and excisional tumor specimens.ConclusionIntratumoral heterogeneity determines discordant results of diagnostic tests for Human Epidermal Growth Factor Receptor (HER)2in gastric cancer specimens, The clinical significance and impact of intratumoral HER2expression heterogeneity on treatment outcome in gastric cancer require further studies. |
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