Significance of Genetic Abnormalities of p53 Protein in Slovenian Patients with Gastric Carcinoma

In the 1980s, stomach cancer was the most frequent type of cancer worldwide and, although its incidence has gradually declined in developed countries, it still remains one of the leading causes of mortality worldwide, with a modest 5-year survival of about 25% (1,2). In general, it is still the one of the leading cause of cancer-related death, surpassed only by lung and breast cancer (3,4). According to the classification by Lauren (5), stomach cancer is classified into two main histological types: diffuse and intestinal. Particular combinations of genetic and epigenetic changes differ in both subtypes, although a few of them appear to be common, as shown by several studies in the last decade (6-8). Namely, a significant proportion of intestinal type carcinomas progress to diffuse types, and in individuals a large number of tumors could also be comprised of a mixture of both cellular subtypes (9,10). In addition to hypermethylation of several genes and loss of heterozigosity, abnormalities of p53 tumor suppressor gene are the most evident genetic changes found in both types of gastric cancer, which is in accordance with generally accepted opinion that genetic changes of p53 are one of the most prevalent alterations in human cancers (8,10,11). The main mechanisms of inactivation in gastric cancer are loss of heterozigosity, mutations, and frame shift deletions (8,9). These abnormalities occur in 46.6 to 74% of gastric cancers, regardless of the histological subtype. They are also frequently observed in pre-cancerous lesions such as intestinal metaplasia and dysplasia, which are precursors of the intestinal type of gastric cancer (9,12). Most mutations of p53 gene or genetic and/or epigenetic changes of upstream and/or downstream located genes in the p53 network result in a loss of function of the wild-type gene product. However, most but not all mutant p53 proteins have a prolonged half-life and accumulate in cells (13,14). Both p53 accumulation and its absence in the nucleus of malignant cells could thus be used as a valuable prognostic marker and predictor of clinical outcome of gastric tumors. Namely, several studies have shown the association of p53 mutations with particular histological type of gastric cancer, age of the patients at the onset of malignancies, and poor response to the treatment (9,14-16). In the present study, we studied a series of 230 gastric carcinomas, collected in a period from 1983 to 2001. We wanted to combine molecular genetic analysis data on p53, such as expression, loss of heterozygosity (LOH), microsatellite instability (MSI), and mutational status with tumor descriptive characteristics in order to discern the value of p53 as a molecular marker for diagnosis and/or prognosis in this type of cancer. We showed that at least one of the selected clinical or histopathological features might be associated with genetic variables such as p53 expression, loss of heterozigosity, or microsatellite instability, and could thus in combination improve the determination of biological feature and/or prognosis of gastric malignancy.