Altered distribution of beta-catenin, and its binding proteins E-cadherin and APC, in ulcerative colitis-related colorectal cancers.

The beta-catenin pathway plays a central role in transcriptional signaling and cell-cell interactions in colonic epithelium. Alterations of the expression of beta-catenin, and its binding partners E-cadherin and the adenomatous polyposis coli protein (APC), are frequent events in sporadic colorectal cancer. Ulcerative colitis (UC)-related cancers originate in a field of chronic inflammation and therefore may have different alterations in the beta-catenin pathway than sporadic cancers. To test this hypothesis, expression and subcellular localization of beta-catenin, E-cadherin, and APC were detected by immunohistochemistry in paraffin sections from 33 UC-related and 42 sporadic colorectal cancers. Although beta-catenin and E-cadherin expression were predominantly limited to the lateral cell membrane in normal colonic epithelium, both tumor groups showed an overall shift from membranous to cytoplasmic expression for these proteins. An increase in nuclear localization of beta-catenin and a decrease in cytoplasmic APC expression also were seen in both cancer groups compared with normal epithelium. Abnormal beta-catenin expression was more closely linked to E-cadherin alterations in UC-related cancers than in sporadic cancers. In contrast, abnormal beta-catenin expression was more closely linked to APC alterations in sporadic cancers than in UC-related cancers. These data suggest that alterations of the beta-catenin pathway are important in both UC-related and sporadic colorectal cancers. However, differences in the expression patterns of beta-catenin, E-cadherin, and APC between UC-related and sporadic colorectal cancers suggest that the specific alterations in this pathway may differ in these two cancer groups.

Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization.

Both ulcerative colitis (UC)-related and sporadic colorectal cancers are thought to evolve through a multistep process of genomic instability, accumulation of genomic alterations, and clonal expansion. This process may involve different genomic changes in UC-related cancers than in sporadic cancers because of the origin of UC-related cancers in an inflammatory field. This study was designed to define the specific genomic events occurring in UC-related cancers. Comparative genomic hybridization (CGH) was performed on 32 UC-related and 42 stage-matched sporadic colorectal cancers. The mean number of chromosomal alterations per case was similar in the UC-related and sporadic tumor groups (8.6 in UC, 8.1 in sporadic). The 2 tumor groups shared many chromosomal alterations: losses on 18q (78% UC v69% sporadic), 8p (53% v50%), 17p (44% v57%), and gains on 8q (63% v45%), 20q (44% UC v67%), and 13q (44% UC v38%). However, differences in the frequency and timing of specific alterations were observed. Chromosome 5q was lost in 56% of UC-related but in only 26% of sporadic cancers. Alterations of chromosome 8 were associated with stage progression in UC-related, but not in sporadic cancers. In contrast, 18q loss was associated with stage progression in sporadic cancers only. Thus, differences in the frequency and timing of individual chromosomal alterations suggest that genetic progression in these 2 tumor groups may follow multiple pathways.