Immunohistochemical expression of cell-cycle proteins in gastric precancerous lesions.
ABSTRACT The early indicator for the subject predisposed to gastric cancer is abnormal proliferation of gastric epithelial cells, such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, which have been considered as precancerous lesions of gastric cancer. To determine whether p53 protein, cyclins D1, and D3, and p27(kip1) play a role in the carcinogenesis pathway of gastric cancer, we performed an immunohistochemical study of their expression in gastric precancerous lesions.
A total of 1 45 endoscopic gastric biopsy specimens of AG, IM, and gastric dysplasia were studied. These molecular markers were localized by immunohistochemistry.
P53 was expressed in 15% of cases with gastric dysplasia and not in the pre-dysplastic stages of the gastric mucosa. All cases were concerning high-grade dysplasia. Cyclin D1 protein was almost undetectable in the precancerous lesions of gastric cancer. Cyclin D3 protein overexpression was seen in 10% of biopsies with IM, and 50% of biopsies with gastric dysplasia. High expression of p27(kip1) protein was demonstrated in all cases of chronic gastritis. As atrophy, IM, and dysplasia develop, expression of p27(kip1) protein is suppressed. In total, 15% of dysplastic cases showed no expression of p27(kip1) protein.
(i) P53 mutation must be a late event during the development of gastric cancer. (ii) Cyclin D1 protein overexpression may not play a role in the progression from normal to neoplastic gastric mucosa, while overexpression of cyclin D3 is an earlier event during gastric carcinogenesis, and its role must be further evaluated. (iii) Reduced expression of p27(kip1) is a rather early event in gastric tumorigenesis, before dysplastic changes occur.
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ABSTRACT: The mainstream carcinogenic processes involved within the gastrointestinal tract are characterized by phenotypic multistep progression cascades that eventually result in full-blown cancers. In this scenario, the understanding of the molecular dysregulations underlying the precancerous lesions is increasing but still remains incomplete. However, in recent years, the enthusiastic rise of innovative technologies (i.e., next-generation sequencing, high-throughput microarray analysis, mass spectrometry based proteomics) and the unexpected discovery of new classes of biomarkers (i.e., miRNA, long-noncoding RNAs) prompted new strength in the exploration of the accurate and comprehensive molecular characterization of premalignant and malignant neoplastic lesions. The challenge ahead lies in the reliable identification of disease progression-specific targets to enable molecular testing in the clinical management of the secondary prevention of gastrointestinal cancers.Best practice & research. Clinical gastroenterology 04/2013; 27(2):159-69. · 2.48 Impact Factor
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ABSTRACT: Background and study aimsAlthough it is fairly well accepted that Helicobacter pylori infection (H. pylori) plays a significant role in causing gastric cancer, the exact mechanisms involved in its pathogenesis are unclear and there is controversial data about the state of chronic gastritis and the precancerous lesion after treatment of H. pylori. This study was designed to investigate the relationship between H. pylori infection, the activity of chronic gastritis and oncogenes before and after treatment of H. pylori.Arab Journal of Gastroenterology 12/2009;
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ABSTRACT: There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC). HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes. Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P < 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene. Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.Gastric Cancer 11/2013; · 4.83 Impact Factor