Section 7 -

Molecular Basis of Gastric Dysplasia Robert D. Odze, M.D. Jonathan Glickman, M.D., Ph.D. Mark Redston, M.D.

Although there are a significant number of studies regarding molecular alterations in gastric cancer, studies investigating the progression from premalignant precursors are more limited (reviewed in references 1, 2, 3, 4, 5) . The findings are presented in Table 1. Progression markers in gastric intestinal metaplasia The number of studies that have investigated genetic alterations in non-dysplastic gastric mucosa with intestinal metaplasia are limited. Shiao et al found p53 mutations in 6/12 (50%) non-dysplastic cases with intestinal metaplasia adjacent to carcinoma [6]. Accumulation of p53 in intestinal metaplasia has also been demonstrated by immunohistochemical methods, and was most common in Type III metaplasia [7]. Microsatellite instability has been found in cases with intestinal metaplasia, both with and without cancer. Leung et al found high frequency microsatellite instability in 7/75 samples with intestinal metaplasia [8]. These results are further supported by the finding of MLH1 promoter methylation in intestinal metaplasia [9]. In addition, promoter methylation can be identified at a number of other loci in intestinal metaplasia, including p16 [9]. Finally, COX-2 expression has been identified in intestinal metaplasia, raising the possibility that COX-2 inhibitors agent may be effective in chemoprevention [10]. Progression markers in gastric adenomas and dysplasia In a recent investigation, Lee et al found that APC gene mutations were more common in adenomas or flat dysplasia without associated adenocarcinoma (59/78) compared to adenoma/dysplasia with adenocarcinoma (1/30) or adenocarcinomas without adenoma/dysplasia (3/69; P < 0.001) [11]. In contrast, high frequency microsatellite instability was more frequent in adenoma/dysplasia with associated adenocarcinoma (6/35) than in adenomas/dysplasia without associated carcinoma (2/75; P = 0.01). These findings were interpreted as suggesting that adenomas without APC mutations, or with high frequency microsatellite instability, may have a different biologic behavior, and may be more likely to progress to cancer. Familial diffuse gastric carcinoma In addition to an increased risk of gastric cancer in families with hereditary non-polyposis colorectal cancer, gastric cancer can also be inherited in an autosomal dominant-like manner. In this setting, the cancers are usually of the diffuse type, and are associated with germ line inherited inactivating mutations in E-cadherin [12, 13]. Prophylatic gastrectomy specimens from individuals known to carry germ line E-cadherin mutations have revealed focal mucosal signet ring cell collections consistent with early carcinoma [14, 15]. Molecular basis of fundic gland polyps Fundic gland polyps are a well recognized feature of familial adenomatous polyposis (FAP), which is caused by germ line mutations in the APC gene [16]. In the setting of FAP, most fundic gland polyps show inactivation of the second copy of the APC gene by somatic mutation [17]. There is no correlation between the presence of somatic mutations and dysplasia, which commonly occur in FAP-associated lesions. Fundic gland polyps also occur sporadically. In this setting, APC mutations are uncommon [17]. However, beta-catenin mutations are found in the majority [18, 19], resulting in nuclear beta-catenin stabilization (similar to the effect of APC mutation). Although dysplasia is uncommon in sporadic fundic gland polyps, those that develop dysplasia are much more likely to have APC mutations, suggesting a link between APC mutations and the development of dysplasia in fundic gland polyps [20]. Table 1: Molecular Alterations In Gastric Dysplasia And Adenocarcinoma Molecular Alteration Biologic Role Non-dysplastic atrophic and metaplastic mucosa p53 inactivation/mutation; rare DNA damage response; de-regulation of cell cycle arrest and apoptosis Microsatellite instability genome instability Methylation of MLH1 and other loci (including p16) silencing of tumor suppressors Gastric Dysplasia 17p LOH/p53 inactivation/mutation DNA damage response; de-regulation of cell cycle arrest and apoptosis Gastric Adenoma/Dysplasia 17p LOH/p53 inactivation/mutation; 30% DNA damage response; de-regulation of cell cycle arrest and apoptosis 5q LOH/APC inactivation/mutation; common WNT signalling, cell adhesion Adenocarcinoma c-met/HGF amplification/overexpression growth factor receptor stimulation K-sam amplification/overexpression (diffuse >> intestinal) growth factor receptor stimulation Cyclin E amplification/overexpression; 15% cell cycle regulator 17p LOH/p53 inactivation/mutation; 60% DNA damage response; de-regulation of cell cycle arrest and apoptosis 5q LOH/APC inactivation/mutation (intestinal >> diffuse) WNT signalling, cell adhesion 18q LOH/DCC inactivation; 60% inactivation of a variety of tumor suppressor loci References Leung, W.K. and J.J. Sung, Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther, 2002. 16(7): p. 1209-16. (7): p. 971-3. Wener, M., et al., Gastric adenocarcinoma; pathomorphology and molecular pathology. J Cancer Res Clin Oncol, 2001. 127(4):p.207-16. El-Rifai, W. and S.M. Powell, Molecular biology of gastric cancer. Semin Radit Oncol, 2002. 12(2):p. 128-40. Fiocca, R., et al., Molecular mechanisms involved in the pathogenesis of gastric carcinoma: interactions between genetic alterations, cellular phenotype and cancer histiotype. Hepatogastroenterology, 2001. 48(42): p. 1523-30. Ebert, M.P. and P. Malfertheiner, Review article: Pathogenesis of sporadic and familial gastric cancer-implications for clinical management and cancer prevention. Aliment Pharmacol Ther, 2002. 16(6): p. 1059-66. Shiao, Y.H., et al., p53 alterations in gastric precancerous lesions. Am J Pathol 1994. 144(3): p. 511-7. Wu, M.S., et al., Overexpression of p53 in different subtypes of intestinal metaplasia and gastric cancer. Br J Cancer, 1998. 78(7): p. 971-3. Leung, W.K., et al., Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol, 2000. 156(2): p. 537-43. Kang, G.H., et al., CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res, 2001. 61(7): p. 2847-51. Sung, J.J., et al., Cyclooxygenase-2 expression in Helicobacter pylori Lee, J.H., et al., Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. Am J Pathol, 2002. 161(2): p. 611-8. Nature, 1998. 392(6674): p. 402-5. Guilford, P.J., et al., E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat, 1999. 14(3): p. 249-55. Huntsman, D.G., et al., Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. 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