Microsatellite instability in early gastric cancer.

Microsatellite replication errors (RERs), consisting in random tumour-associated allele contractions or expansions, represent a frequent genetic alteration in gastric cancer and appear to be associated with important clinicopathologic parameters. To verify the role of microsatellite instability in the initial phases of gastric carcinogenesis, we analysed the status of II microsatellites in paired microdissected samples of tumour and unaffected mucosa from 30 cases of early gastric carcinoma. Fifteen tumours (50%) demonstrated RERs: these included 7 cases with RERs at one locus and 8 cases with RERs at 2 or more loci. Cases with 2 or more RERs were more frequent among intramucosal tumours, compared to tumours with submucosal spread (43% vs. 12%) and among tumours staged T1NOMx, compared to tumours staged T1N1Mx (35% vs. 0%). RER-positive microsatellite typings were statistically more frequent among tumours with intramucosal extension, lower stage (T1NOMx) and excavated growth pattern (macroscopic type III), compared to tumours with submucosal extension, higher stage (T1N1Mx) and elevated, flat or depressed growth patterns (macroscopic types IIa-IIb-IIc respectively). The above findings indicate that microsatellite instability occurs early in the progression of sporadic gastric cancer and tends to be associated with good prognostic indicators.

Novel allele of the hMLH1 gene bearing a TTC deletion in the 3' untranslated region.

SSCP analysis of the hMLH1 gene in two kindreds affected by hereditary nonpolyposis colorectal cancer (HNPCC) revealed the presence of unique conformers in all patients affected by colorectal cancer. Sequence analysis of the corresponding region of the gene revealed a 3 base pairs deletion within a TTC tandem repeat (G TTC TCC T-->G TTC T) beginning 29 base pairs downstream of the termination codon of the gene in the 3' untranslated region. This deletion causes the loss of an MboII restriction site. Analysis extended to 113 healthy unrelated individuals and 27 unrelated HNPCC patients demonstrated the occurrence of this novel variant of the hMLH1 gene at similar frequencies in unrelated HNPCC patients (3.7%) and in control individuals (2.2%). The allele bearing the TTC deletion appears to be expressed at levels comparable to those of the wild-type allele.

Integrin b4 expression in peripheral-nerve tumors.

The alpha 6 beta 4 integrin complex is expressed in epithelial, endothelial and nerve cells. We analyzed the immunohistochemical expression of the beta 4 subunit in normal peripheral nerves, in neurofibromas associated with type 1 neurofibromatosis and in sporadic neurofibrosarcomas. In normal peripheral nerves (4 samples), the beta 4 integrin was diffusely expressed at the level of the perinevrium and at the interface between axons and Schwann cells. In neurofibromas (6 cases), beta 4 was undetectable or markedly decreased relative to normal peripheral nerves. Neurofibrosarcomas (3 cases) were immunohistochemically negative for beta 4 expression. These observations suggest that a down-regulation of the alpha 6 beta 4 integrin is associated with the neoplastic progression of peripheral nerve tumors.

Integrin Beta-4 expression in colorectal-cancer.

Integrin alpha 6 beta 4 plays an important role in the interaction of epithelia with basement membranes, and its expression appears to be profoundly altered during tumor progression. Using a quantitative immunochemical assay, we investigated the expression of the beta 4 subunit associated with alpha 6 in 25 primary carcinomas, and in matching normal mucosae. alpha 6 beta 4 was expressed in all the carcinoma and mucosa samples. The highest beta 4 levels were detected in tumors at high clinical stage (Dukes' stage C). Furthermore, beta 4 reactivity inversely correlated with the degree of differentiation. By immunohistochemistry,beta 4 expression was particularly strong in the epithelium lining the upper third of the crypts and the absorbing surface of normal mucosa. In villous adenomas, beta 4 immunostaining tended to be enhanced in the epithelium lining the outer surfaces of neoplastic villi, but only 5 of 8 samples tested scored positive. In carcinomas, beta 4 expression was detected in 18 of 21 samples tested, and was strongly influenced by the pattern of tumor growth and by the type and level of differentiation. Carcinomas, or areas of carcinomas, with cohesive and differentiated growth pattern demonstrated weak beta 4 expression at the tumor-stroma interface. Carcinoma cells at the lumenal surface of the intestine, and carcinomas, or areas of carcinomas, composed of small clusters of cells surrounded by stroma, demonstrated strong beta 4 expression. Altogether, our observations indicate that in colorectal tumors the expression of the beta 4 subunit is strongly influenced by microenvironmental factors and tends to increase in high stage, poorly differentiated lesions.