Section 4 -

Molecular Basis of Squamous Dysplasia and Carcinoma of the Esophagus Robert D. Odze, M.D. Jonathan Glickman, M.D., Ph.D. Mark Redston, M.D.

The molecular basis of squamous cell carcinoma and associated preneoplastic precursors are summarized in Table 2. Molecular Diagnostic Applications in Squamous Dysplasia The only molecular alteration that has been significantly studied in premalignant squamous lesions of the esophagus is p53 [74]. This gene is mutated in a high proportion of squamous cell carcinomas, particularly in regions of high endemic risk [74]. In such cases, p53 immunohistochemical staining reveals nuclear positivity (consistent with mutation) in dysplasia, and in focal areas of non-dysplastic squamous epithelium [75]. Limited molecular analyses have identified p53 mutations in some of these foci. These findings support the observations of other studies [76, 77, 78]. Although abnormalities in p53 expression have been prospectively identified in non-dysplastic biopsies from individuals at risk for squamous esophageal carcinoma [79], additional studies are required to characterize the utility of p53 as a biomarker for progression in squamous neopalsia of the esophagus. There is some preliminary evidence in the possible utility of several other markers. Expression of p63 and deltaNp63 isoforms has been detected at very high levels in most squamous low and high grade intraepithelial neoplasms [80]. Molecular Basis of Dysplasia and Adenocarcinoma of the Stomach 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 [81, 82, 83, 84, 85]) . The findings are presented in Table 3. Molecular Diagnostic Applications in Gastric Premalignant Neoplasia Progression Markers in Gastric Intestinal Metaplasia The number of studies that have investigated genetic alterations in non-dysplastic gastric mucosa with intestinal metaplasia are quite limited. Shiao et al found p53 mutations in 6/12 (50%) non-dysplastic caases with intestinal metaplasia adjacent to carcinoma [86]. Accumulation of p53 in intestinal metaplasia has also been demonstrated by immunohistochemical methods, and was most common in Type III metaplasia [87]. 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 [88]. These results are further supported by the finding of MLH1 promoter methylation in intestinal metaplasia [89]. In addition, promoter methylation can be identified at a number of other loci in intestinal metaplasia, including p16 [89]. Finally, COX-2 expression has been identified in intestinal metaplasia, raising the possibility that COX-2 inhibitors agents may be effective in chemoprevention [90]. 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) complared to adenomas/dysplasia with adenocarcinoma (1/30) or adenocarcinomas without adenoma/dysplasia (3/69; P < 0.001)[91]. In contrast, high frequency microsatellite instability was more frequent in adenomas/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 [92, 93]. 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 [94, 95]. Molecular Aspects 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 [96]. In the setting of FAP, most fundic gland polyps show inactivation of the second copy of the APC gene by somatic mutation [97]. There is no correlation between the presence of somatic mutations and dysplasia, which commonly occurs in FAP-associated lesions. Fundic gland polyps also occur sporadically. In this setting, APC mutations are uncommon [97]. However, beta-catenin mutations are found in the majority [98, 99], 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 [100]. Table 1. Molecular alterations in Barrett's esophagus Molecular Alteration Biologic Role Non-dysplastic Barrett's SRC overexpression tyrosine kinase in EGF signalling pathway 11q13 amplification/Cyclin D1 overexpression stimulates cell cycle progression Bcl2 overexpression inhibits apoptosis 13q14 deletion/Rb inactivation de-regulation of cell cycle progression and apoptosis 9p21 deletion/p16 inactivation CDK inhibitor; de-regulation of cell cycle progression 5q21 deletion/APC inactivation WNT signalling; cell adhesion 18q deletion/DCC (and other) gene loss some genes involved in TGFB signalling 17p13 deletion/p53 inactivation DNA damage response; de-regulation of cell cycle arrest and apoptosis Aneuploidy end result of chromosomal instability Dysplastia KRAS activating mutations signal transduction; growth stimulation p21 overexpression CDK inhibitor; may reflect underlying p53 abnormalities telomerase overexpression maintains chromosomes; important for cell immortality p27 loss or cytoplasmic localization CDK inhibitor; de-regulation of cell cycle Adenocarcinoma 17q21 amplification/HER2 overexpression transmembrane receptor; external growth signals 7p12-13 amplification/EGFR overexpression transmembrane receptor; external growth signals 2p13 amplification/TGF-α overexpression ligand for EGFR; stimulates cell division MDM2 overexpression negative regulation of p53 19q12 amplification/Cyclin E overexpression stimulates cell cycle progression E and P cadherin loss increased cell migration; metastasis Other chromosomal deletions (including 3p, 4p, 4q, 7q, 12q, 17q, 22q) and amplifications (including 2p, 8q, 20q) unknown tumor suppressor genes and oncogenes Table 2. Molecular alterations in squamous neoplasia of the esophagus Molecular Alteration Biologic Role Non-dysplastic squamous epithelium p53 immunoreactivity DNA damage response; de-regulation of cell cycle arrest and apoptosis Squamous Dysplasia 17p13 LOH/p53 mutation DNA damage response; de-regulation of cell cycle arrest and apoptosis Squamous Cell Carcinoma 11q13 amplification/Cyclin D1 overexpression stimulates cell cycle progression 7p12-13 amplification/EGFR overexpression transmembrane receptor; external growth signals 8q24.1 amplification/c-myc overexpression transcriptional activation 9p21 deletion/p16 inactivation CDK inhibitor; de-regulation of cell cycle progression 13q14 deletion/Rb inactivation de-regulation of cell cycle progression and apoptosis Other chromosomal deletions (including 1p, 3p, 5q, 11q, and 18q) unknown tumor suppressor genes and oncogenes References Beilstein, M. and D. 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