Histological grade and type of growth of gastric cancer in connection with E-cadherin gene mutations in sporadic gastric cancers


Ulatowska-Białas, Magdalena


mutations ; immunohistochemistry ; gastric cancer ; E-cadherin


the study objectives Gastric adenocarcinoma is the most frequent malignant neoplasm ofthis organ, typically diagnosed in people older than 65 years old. Despite the declining incidence of gastric cancer it remains one of the most common malignant neoplasm being responsible for a significant percent of cancer-related deaths. The incidence of gastric carcinoma and the relative frequency of its particular histological types show marked geographical variability. Etiopathogenesis of gastric cancer is connected to multiple environmental agents which influence each other and mutually modulate their effects, and are further influenced by individual genetical predispositions. The best known environmental agents are: special dietary habits and Helicobacter pylori infection, especially when acquired in childhood and/or caused by cag-A strains. A marked inter- and intraindividual variability of gastric carcinoma histological pattems resulted in the development ofnumerous histological classifications of this neoplasm. The most widely accepted classifications system are: Lauren, Goseki,WHO and Ming classifications. Bormann classifications describes macroscopic forms of gastric cancer infiltrates. Most accepted gastric cancer classifications do not posses prognostic value. Prognosis in gastric cancer correlates with clinical stage of the disease - five years survival rate in so-called ea ; rly gastric cancer is approximately 90%, were as in advanced stages five years survival rate declines to 10-15%. There are probably numerous additional factors which can influence the prognosis in gastric cancer patients: among them are changes in E-cadherin-catenin unit (ECCU) proteins. These proteins are normally responsible for the maintenance of intracellular adhesion in epithelial tissues and for providing signal transduction between epithelial cells. the aim of the study Status of the CDH I gene coding E-cadherin protein and the expression of Ecadherin and B-catenin proteins were investigated in the group of 84 sporadic, advanced gastric cancers. The correlations between E-cadherin gene mutations, disturbances of immunohistochemical expression ofECCU proteins and histological features of neoplasm: cancer differentiation, type of growth, presence and composition of inflammatory in fil tra te, angiogenesis, expression of p-53 and survivin proteins and the survival interval after operation were investigated. materials and methods The materiał was collected from the patients operated for gastric cancer between 1996-2000 in the First Surgical Department in Cracow. lt consisted of 84 advanced, sporadic gastric cancers. Basic histopathological techniques: hematoxilin-eosin and Alcian-PAS staining as well as immunohistochemistry with specific, monoclonal antibodies and mo ; lecular techniques: PCR-SSCP reactions, which allowed to detect mutations. and to loca te them in a proper ex on of the investigated gene were used in this work. Statistical analysis was done using computer program: Statistica for Windows 6.0. results Bands pattem analysis revealed presence of CDH I gene mutations in 13% of investigated gastric cancers. When only so-called diffuse and mixed types were taken under consideration, the mutations were present in 19% of investigated cases. Disturbances in expression of E-cadherin protein were detected immunohistochemicaly in about 20% ( 17 cases) and of B-catenin protein in about 19% (16 cases). Statistically significant correlation between the presence ofEcadherin gene mutation and disturbances in E-cadherin protein expression was found. It was noticed that a part of sporadic, advanced gastric cancers with detected mutation in CDH1 gene do not show abnormal expression of the E-cadherin protein. Some cases with unmutated E-cadherin gene showed a deranged protein expression, most probably due to the epigenetic factors. Deranged expression of proteins belonging to the ECCU identifies a gro up of patients with poorer overall survival. The E-cadherin mutation however, does not have any prognostic impact. In the present study it was possible to confirm the value oftraditional prognostic factors: the lymph node status, distant metast ; ases, and the tumor stage. The Goseki classification was proved to have a prognostic impact by the Cox proportional hazard model. There was a trend toward poorer survival in the cases demonstrating the nuclear accumulation of the p53 protein. No prognostic significance was proven for the intensity of angiogenesis, survivin expression, inflammatory infiltrate at the tumor invasion front, and histological variability within an individual tumor. the most important conclusion of the work Disturbances in expression of E-cadhcrin and/or B-catenin protcins detected immunohistochemicaly in gastric cancer infiltrate define the group of patients with poorer overall survival.

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Level of degree:

2 - studia doktoranckie

Degree discipline:

onkologia ; choroby układu trawiennego

Degree grantor:

Wydział Lekarski


Stachura, Jerzy



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Praca doktorska

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