Fig. 3.26 A, B Fundic gland polyp. Cystic glands are typical.

ment {1288}. Loss of a locus on 7q (D7S95) associates with peritoneal metastasis.

The frequency of MSI in sporadic gastric carcinoma ranges from 13% to 44% {1713}. MSI+ tumours tend to be advanced intestinal-type cancers. The degree of genome-wide instability varies with more significant instability (e.g., MSI-H: > 33% abnormal loci) occurring in only 16% of gastric carcinoma, usually of the subcardial intestinal or mixed type, with less frequent lymph node or vessel invasion, prominent lymphoid infiltration, and better prognosis {430}. Loss of either hMLH1 or hMSH2 protein expression affects all MSI-H cases {654} suggesting

Fig. 3.27 Peutz-Jeghers polyp with hyperplastic glands.

inactivation of both alleles by mechanisms such as hypermethylation {1050, 510}.

Genes with simple tandem repeat sequences within their coding regions that are altered in MSI+ tumours include the TGF-p II receptor, BAX, IGFRII, hMSH3, hMSH6, and E2F-4. A study of gastric cancers displaying the MSI-H phenotype reveal that a majority contain mutated TGF-p type II receptors in a polyadenine tract {1420, 1462}. Altered TGF-p II receptor genes can also be found in MSI-lesions. Allelic loss of TP53 occurs in > 60% of cases and mutations are identified in approximately 30-50% of cases depending on the mutational screening method and sample sizes {729, 1937}. TP53 mutations are identifiable in some intestinal metaplasias; {497} most alterations affect advanced tumours. TP53 mutations in gastric lesions resemble those seen in other cancers with a predominance of base transitions, especially at CpG dinucleotides. Immunohistochemi-cal analyses to detect TP53 overexpression can indirectly identify TP53 mutations but do not have consistent prognostic value in gastric carcinoma patients {557, 766}. Finally, with respect to TP53, there is a polymorphism in codon 72 encoding a proline rather than an arginine that strongly associates with antral cancers {1735}. Sporadic gastric carcinomas, especially diffuse carcinomas, exhibit reduced or abnormal E-cadherin expression {1196, 1135}, and genetic abnormalities of the E-cadherin gene and its transcripts. Reduced E-cadherin expression is associated with reduced survival {848}.

E-cadherin splice site alterations produce exon deletion and skipping. Large deletions including allelic loss and missense point mutations also occur; some tumours exhibit alterations in both alleles {135}. Somatic E-cadherin gene alterations also affect the diffuse component of mixed tumours {1136}. Alpha-catenin, which binds to the intracellular domain of E-cadherin and links it to actin-based cytoskeletal elements, shows reduced immunohistochemical expression in many tumours and correlates with infiltra-tive growth and poor differentiation {1189}. Beta catenin may also be abnormal in gastric carcinoma. There is evidence of a tumour suppressor locus on chromosome 3p in gastric carcinomas {893, 1688}. This area encodes the FHITgene. Gastric carcinomas develop abnormal transcripts, deleted exons {1411}, a somatic missense mutation in exon 6 and loss of FHIT protein expression {102}. Somatic APC mutations, mostly missense in nature and low in frequency, affect Japanese patients with in situ and invasive neoplasia {1309}. Significant allelic loss (30%) at the APC loci suggest that there is a tumour suppressor gene important in gastric tumourigenesis nearby. Indeed, alternative loci have been mapped to commonly deleted regions in gastric carcinomas {1891}. Amplification and overexpression of the c-met gene encoding a tyrosine kinase receptor for the hepatocyte growth factor occurs in gastric carcinoma {976}. Other growth factor and receptor signal systems that may be involved include epidermal growth factor, TGF-alpha, interleukin-1-a, cripto, amphiregulin, platelet-derived i «A "Ivw iPlrí '

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