GENETIC ALTERATIONS IN GASTRIC PRECANCEROUS LESIONS

Summary: Genetic alterations in gastric precaneemus lesiona: To investigate the occurrence of 1 7p(p53) loss of heterozygosity (LOH) and increased 4N or aneuploidy in gastric precancerous lesions (GPL), and their association with llelicohacter pvlori (Il pylori) inl'ection. A total of 78 gastric mucosa! biopsy specimens, including 10 normal mucosa and 68 gastric precancerous lesions [chronic atrophie gastritis (CA(J, n=20), intestinal metaplasia (IM, ?=?2), low grade dysplasia (L(JD, n=l5), and high grade dysplasia (HGD, n=21)] were studied using PCR and flow cytometry. A modified (iiemsa staining technique was used to detect H pylori. The study was performed in Erzurum Nuinune Hospital between 2007 and 20(W. l7p(p53)LOH was observed in (1/20) 5% of CAG, in ( 2/12) 16% oflM, in (3/15) 20% of LCD and in ( 1 1/ 21 ) 53% of HGD. There was correlation between prevalence of 1 7p(p53) LOH and hislologieal type of GPL (/>=0.004). Similarly, increased 4N or aneuploidy was detected in ( 1/20) 5%, of CAG, in ( I/ 1 2) 8% of IM, in (2/15) 13% of LGD and in (9/21 ) 43% of HGD. The correlation was found between aneuploidy and histologica! type of GPL (/>=0.0(I9). However, there was no correlation between presence of H pylori infection in histologica! type of GPL (/>=0.921). On the other hand, a significant association was found between increased 4N or aneuploidy and 1 7p(p53)LOH in all of GPL (P=(LOOOI ). However, there was no statistically significant association between // pylori infection and l7p(p53)LOH or increased 4N/ aneuplody in GPL. I7p(p53) LOH and increased 4N or aneuploidy are closely related to the early stages of gastric carcinogenesis. Key-words: p53 gene - Loss of helerozygosity - increased 4N - Aneuploidy - Helicobacter pylori - Gastric precancerous lesions. INTRODUCTION The development of gastric cancer in humans has been shown to be a multistep process, ranging from chronic gastritis to atrophy, intestinal metaplasia, dysplasia and finally gastric cancer (7, 53, 59). In the multistep process of gastric carcinogenesis, the bacterium Helicobacter pylori plays a major etiological role and has recently been classified as a type-I carcinogen (17). H pylori infection is generally believed to be the initial trigger of the cascade of this process, beginning with a chronic active inflammatory response of the mucosae and subsequently progressing to gastric atrophy, intestinal metaplasia, dysplasia and ultimately to cancer (8). Mutation or allelic deletion of p53 gene appears to play an important role in the development of human carcinoma (16, 18, 41). It has been established that accumulation of wild-type p53 protein results in two pathways; cell cycle arrest and programmed cell death, which together are involved in tumor suppressor functions (19). Therefore mutation of p53 leads to disruption of these pathways, a selective growth advantage for tumor cells and loss of function may result in increased proliferation activity and tumor development (60). p53 gene is a cell cycle control gene that prevents cells with DNA breaks from entering DNA synthesis where the breaks could be replicated cause chromosome damage and lead to progressive genetic instability and cancer (27). The p53 gene is located at chromosome 17pl3 (15). Inactivation of the p53 gene involves a two-step mechanism consisting of a point mutation on one aliele, consistent with Knudson's two-hit hypothesis. One copy is typically inactivated by mutation, whereas the second copy is lost by a mechanism called 1 7p loss of heterozygosity (LOH). p53+/+ cells respond to genotoxic injury by undergoing cell cycle arrest or programmed cell arrest or programmed cell death. However, p53-/- cells do not arrest cell cycle in the presence of DNA damage and continue to proliferate, accumulating genetic lesions that lead to cancer (3, 19, 38). Cell populations making up a tumor present morphologic and functional features that vary with time as a result of different selective stimuli. …