Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of colorectal cancer. This increased cancer risk is thought to result from the cellular damage induced by the inflammatory field. The aim of this study was to determine the pattern and time course of genomic instability occurring in UC-related neoplasia. Sites of cancer, dysplasia, and nondysplasia from 14 UC colectomy cases containing cancer were analyzed for chromosomal alterations by comparative genomic hybridization (CGH) and for microsatellite instability using a series of 10 microsatellite markers. Clonal chromosomal alterations were present in 85% of cancer sites, 86% of dysplasia sites, and 36% of nondysplasia sites. Losses of chromosome 18 or 18q and chromosome 5 or 5q were common in cancer and dysplasia and were occasionally detected in nondysplasia. High-level microsatellite instability was detected in the cancer and dysplasia of two cases. Samples that demonstrated high-level microsatellite instability were unlikely to have chromosomal alterations demonstrable by CGH. These studies suggest that the predominant type of genomic instability in UC-related neoplasia is associated with chromosomal alterations and that this type of genomic instability frequently occurs before the development of histologically defined dysplasia.
BACKGROUND Although the APC/β‐catenin pathway is known to play a crucial role in sporadic colorectal carcinogenesis, its influence on ulcerative colitis (UC)–related neoplastic progression is unknown. To elucidate the role of the APC‐/β‐catenin pathway in UC‐related carcinogenesis, the authors identified APC and β‐catenin mutations in a set of UC‐related and sporadic colorectal carcinomas. METHODS The mutational cluster region of APC (codon 1267 to 1529) and exon 3 of the β‐catenin were directly sequenced. RESULTS Only 1 of 30 UC‐related tumors (3%) showed an APC mutation whereas 11 of the 42 sporadic carcinomas (26%) had mutations within the mutational cluster region. Within the sporadic carcinoma group, only 8% of the right‐sided carcinomas showed APC mutations whereas 50% of the left‐sided carcinomas had mutations within the mutational cluster region. None of the tumors in either group showed a β‐catenin mutation. CONCLUSIONS Mutations of the APC and β‐catenin are rare in UC‐related tumors. These genes may be altered because of mutations outside the regions studied, or by epigenetic silencing. Alternatively, other proteins involved in the APC/β‐catenin signaling cascade may be altered, or this pathway may be involved infrequently in UC‐related carcinogenesis. The significant difference in frequency of APC mutations between right‐ and left‐sided sporadic tumors suggests different molecular pathways in these two tumor sites. Cancer 2002;94:1421–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10334
The subretinal delivery procedure in this study was associated with a high rate of retinal perforations (n = 13) and retinal detachments (n = 6). When cells were sequestered in the subretinal space, palucorcel was well tolerated and may be associated with improvements in visual acuity. Larger randomized controlled studies are required to confirm these results. Future studies would require a modified surgical approach.
A 32-year-old man with active Crohn's disease and recurrent small bowel strictures underwent abdominal surgery and was subsequently given total parenteral nutrition (TPN). Severe cholestasis developed and copper was removed from the TPN. Although serum ceruloplasmin levels were within normal limits, 8 weeks after copper removal, he developed pancytopenia. Serum copper levels were severely depressed. Bone marrow biopsy was consistent with copper deficiency; cytoplasmic vacuolization of both myeloid and erythroid precursors, megaloblastic erthropoiesis, and marked hypocellularity were observed. IV replacement with copper sulfate resulted in improvement in the patient's anemia, neutropenia, and thrombocytopenia, but the patient died suddenly from cardiac tamponade. Postmortem examination revealed fibrinous and hemorrhagic pericarditis. Despite the rare occurrence of overt copper deficiency, this case emphasizes the need to recognize copper deficiency as an important etiology of iron-resistant anemia in patients receiving TPN. Furthermore, the relative rapidity with which our patient developed pancytopenia suggests that, in view of the established recommendation that copper be removed from TPN in cholestatic conditions, serum copper levels must be measured periodically.
The -catenin pathway plays a central role in transcriptional signaling and cell-cell interactions in colonic epithelium. Alterations of the expression of -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 -catenin pathway than sporadic cancers. To test this hypothesis, expression and subcellular localization of -catenin, E-cadherin, and APC were detected by immunohistochemistry in paraffin sections from 33 UC-related and 42 sporadic colorectal cancers. Although -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 -catenin and a decrease in cytoplasmic APC expression also were seen in both cancer groups compared with normal epithelium. Abnormal -catenin expression was more closely linked to E-cadherin alterations in UC-related cancers than in sporadic cancers. In contrast, abnormal -catenin expression was more closely linked to APC alterations in sporadic cancers than in UCrelated cancers. These data suggest that alterations of the -catenin pathway are important in both UC-related and sporadic colorectal cancers. However, differences in the expression patterns of -catenin, E-cadherin, and APC between UCrelated and sporadic colorectal cancers suggest that the specific alterations in this pathway may differ in these two cancer groups.
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