Early-onset gastric cancer: On the road to unraveling gastric carcinogenesis

Gastric cancer is the fourth most common malignancy in the world and ranks second in terms of cancer-related death. It is thought to result from a combination of environmental factors and the accumulation of alterations due to increasing genetic instability, and consequently affects mainly older patients, often after a long period of atrophic gastritis. Tumorigenesis is considered a multistep process involving generalized and specific genetic alterations that drive the progressive transformation of cells into cancer. Central to this transformation are genetic or epigenetic changes in the genome which specifically activate oncogenes with a dominant gain of function, and produce alterations in tumor suppressor genes which cause loss of function. There is however by no means a clear-cut pattern of mutations in gastric cancers, and the genetic research can often be hampered by the diversity of changes that are induced by Helicobacter pylori infection, diet, ageing and other environmental factors. Tumors are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship. In order to solve this problem, one approach is to investigate tumors that are less influenced by these environmental factors. Gastric cancers occurring in young patients, known as early-onset gastric cancers, the main subject of this thesis, provide an ideal background on which to try and uncover the initiating stages in gastric carcinogenesis, as the role of genetics is presumably greater than in older patients, with less of an impact from environmental carcinogens. Ultimately they may provide vital information about molecular genetic pathways in sporadic cancers and may aid in the unraveling of gastric carcinogenesis as discussed in chapter 2. In chapter 3 microsatellite instability, is consistently absent in young patients. In chapter 4 we exclude the role of RUNX3 as a tumour suppressor gene in EOGC. In chapter 5 we find that the molecular expression profile of EOGC and conventional gastric cancers differ with EOGCs having a COX-2 Low, TFF-1 expressing phenotype. In chapter 6 we see that the-765 G/C promoter polymorphism in COX-2 is significantly associated with gastric cancer. The expression of low molecular weight isoforms of cyclin E are found to differ in EOGC in chapter 7 and are shown to be a positive prognostic indicator. In chapter 8 we find frequent loss of the putative tumor suppressor gene cdc4/FBXW7 in EOGC and in chapter 9 using representational difference analysis to characterize genetic changes particular to diffuse gastric cancer, a novel amplification at 11p 12-13 was found and was associated with overexpression of CD44v6 especially in EOGC. In Chapter 10, we report the molecular characterization of eight primary gastric carcinomas, corresponding xenografts, and two novel gastric carcinoma cell lines using MS-MLPA, IHC and mutation analysis. In chapter 11 we look at the phenomenon of collision tumors of the gastro-esophageal junction from the molecular genetic prospective and in chapter 12 we describe an inflammatory myofibroblastic tumor with an ALK/TPM3 fusion, a rare tumor which is also found in young people and children.