Surgical Pathology and Current Molecular Aspects of Dysplasia in the GI Tract
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
. 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 . Accumulation of p53 in
intestinal metaplasia has also been demonstrated by immunohistochemical methods, and was most common in
Type III metaplasia . 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 . These results are further supported by the finding of MLH1
promoter methylation in intestinal metaplasia . In addition, promoter methylation can be identified
at a number of other loci in intestinal metaplasia, including p16 . Finally, COX-2 expression has
been identified in intestinal metaplasia, raising the possibility that COX-2 inhibitors agent may be
effective in chemoprevention .
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)
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
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
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 . In the setting of FAP, most fundic gland
polyps show inactivation of the second copy of the APC gene by somatic mutation . 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 . However, beta-catenin mutations are found in the majority
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 .
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|
| 17p LOH/p53 inactivation/mutation ||DNA damage response; de-regulation of cell cycle arrest and apoptosis|
| 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|
| 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|
- 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. N Engl J Med, 2001. 344(25): p. 1904-9.
- Chun, Y.S., et al., Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer, 2001. 92(1): p. 181-7.
- Fodde, R. and R. Smits, Disease model: familial adenomatous polyposis. Trends Mol Med, 2001. 7(8): p. 369-73.
- Abraham, S.C., et al., Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol, 2000. 157(3): p. 747-54.
- Abraham, S.C., et al., Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. Am J Pathol, 2001. 158(3): p. 1005-10.
- Sekine, S., et al., Beta-catenin mutations in sporadic fundic gland polyps. Virchows Arch, 2002. 440(4): p. 381-6.
- Abraham, S.C., et al., Sporadic fundic gland polyps with epithelial dysplasia : evidence for preferential targeting for mutations in the adenomatous polyposis coli gene. Am J Pathol, 2002. 161(5): p. 1735-42.