Molecular and pro-inflammatory genetic profile in gastric carcinomas

Abstract

Gastric cancer is a result from the combination of environmental factors and an accumulation of specific genetic alterations, and affects mainly the older population. It is known that genetic factors play a more important role in early onset gastric cancers than in conventional gastric cancer patients as they have experienced less exposure to environmental factors. It is postulated that EOGC is a key tool in the explanation of the role of genetic changes in gastric carcinogenesis. The specific pathogenetic changes underlying gastric carcinogenesis remain largely unknown. The aim of this thesis is to uncover genetic alterations relevant to gastric carcinogenesis and to elucidate the role of the genes and proteins involved in the progress of cancer in different sub-types of gastric cancers. Additionally, we try to find the best approach for early diagnostics of gastric stump cancers. Gastric cancer is considered a multistep process and multifactor process. An overview of the involved factors as well as important genes in gastric carcinogenesis is provided in chapters 1 and 2. In these chapters the background of gastric cancer is extensively discussed. Additionally in these chapters the concept of early onset gastric cancer is introduced together with the reasoning behind the study of this subtype of gastric cancer. Chapter 3 focuses on a comparison between molecular alterations occurring in primary gastric cancers, corresponding xenografts and gastric carcinoma cell lines. Chapter 4 takes a step towards a better understanding of the progression of gastric carcinogenesis in early onset and conventional gastric cancers. Using Western blot, Q-PCR and sequencing analysis, we examined the correlation between two critical molecules in the development and progression of gastric cancer: COX-2 and E-cadherin. The relationship between these two molecules was examined in vitro in a panel of cell lines and in vivo using tissue microarrays. In chapter 5 we examine the COX-2 -765 G/C promoter polymorphism in different subtypes of gastric cancer. Real time PCR, sequencing analysis and immunohistochemical staining on tissue microarrays were used to find differences between EOGC, conventional gastric cancer and gastric stump cancer. Chapter 6 takes a look into the IL-1B -31 T/C polymorphism distribution in EOGC, conventional and gastric stump cancers using the same techniques as described in chapter 5. Chapter 7 reviews the literature on gastric stump cancer and its precursor lesions and focuses on the reliability of early diagnosis. Finally, chapters 8 and 9 provide brief summaries and a discussion of the thesis (in English and in Dutch respectively).