Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009324 (ulcerative colitis)
 17,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsatellite instability and allelic deletions of tumor suppressor genes have been observed frequently in tumors. Molecular pathogenesis of the development of dysplasia and carcinoma in ulcerative colitis is still unclear. In order to detect microsatellite alterations in ulcerative colitis, we analyzed loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosomes 3, 6, 7, 12, and tumor suppressor gene loci, including p53, APC, and p16, of chronically inflamed, non-dysplastic epithelium after microdissection. Twelve of 13 (92%) cases showed LOH and/or MI at one or more loci. LOH at chromosome 3 and MI at chromosome 12 were observed in 50% and 62%, respectively. However, LOH at p53 and p16 was detected in only one case each. These results suggest that chronic inflammation may initiate microsatellite alteration, which subsequently transform ulcerative colitis to dysplasia or cancer. This finding provides information for the evaluation and treatment of patients with ulcerative colitis.
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PMID:Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis. 985 92

The tumor-suppressive effects of nonsteroidal antiinflammatory drugs (NSAIDs) have been suggested to be due to a reduction in cyclooxygenase (COX)-2 activity, although the effects of COX-2 in the colonic mucosa and in colorectal cancer have not been determined. Ki-67 immunoreactivity in cancers is also attracting attention, as Ki-67 reflects cell proliferation, while p53 immunoreactivity is also of interest, as it reflects the malignancy of colorectal lesions. Accordingly, to determine these correlation, we investigated the distribution and intensity of COX-2, p53 and Ki-67 expression in both cancerous and non-cancerous tissues from patients with sporadic and ulcerative colitis (UC)-associated colorectal cancer. We selected 21 colorectal cancer specimens, obtained by surgical resection or colonoscopic biopsy, from 21 patients, including 3 with UC (13 men and 8 women; aged 42-78 years). Histological examination of hematoxylin and eosin-stained specimens revealed that 9 were well differentiated; 11. moderately differentiated: and 1 was a poorly differentiated adenocarcinoma. We used anti-COX-2, p53, and Ki-67 antisera to perform immunohistochemical staining by the labelled streptavidin biotin method and then assessed and graded the staining intensity and distribution. COX-2 staining was more intense in cancer tissue than in non-cancerous areas. Colorectal cancers associated with UC were not stained intensely. COX-2, p53, and Ki-67 positivity rates in were 38.1%, 38.1%, and 47.6%, respectively. There were no relationships among the distributions or intensities of COX-2, p53, and Ki-67 expression. Our results indicate that colorectal cancer tissues overexpress COX-2, but that there are no relationships between COX-2, p53, and Ki-67 expression, suggesting that COX-2 expression may not be related to cell proliferation or to the grade of malignancy. However, it is necessary to determine whether COX-2 in cancer tissue is involved in carcinogenesis or whether it is simply a product of cancer.
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PMID:Cyclooxygenase (COX)-2 immunoreactivity and relationship to p53 and Ki-67 expression in colorectal cancer. 1086 62

To cast light on accelerated epithelial cell turnover as an important risk factor of dysplasia and carcinoma development in patients with long-standing ulcerative colitis (UC), we examined cell proliferation and cell death, as well as expression of apoptosis-related markers, including p53 and p21WAF1/CIP1, in a series of cases. Biopsy specimens (n = 176; 84, active phase; 92, remission) were endoscopically obtained from 25 Japanese patients with UC. As controls, 68 biopsy specimens of normal mucosa were also examined from 27 Japanese patients with colon polyps. We counted the numbers of mitoses, apoptotic bodies, Ki-67-immunoreactive cells, and p21WAF1/CIP1-immunoreactive cells per 1000 crypt cells and the numbers of p53-positive cells per crypt. All of the indices in active UC were significantly higher than in either remitting UC cases or normal cases (mean mitotic index = 0.52, 0.28, and 0.15%, respectively; apoptotic index = 5.40, 2.91, and 1.30%, respectively; Ki-67 labeling index = 39.5, 28.3, and 26.8%, respectively; p21WAF1/CIP1 labeling index = 33.6, 20.0, and 19.0%, respectively; p53 labeling index = 0.66, 0.13, 0.13 per crypt, respectively). In addition, the mitotic, apoptotic, and Ki-67 labeling indices were increased in remitting UC of more than 10 years' duration, in comparison with those of less than 10 years' duration or the normal group. Immunostaining of serial sections revealed a small number of crypt cells coexpressing p53 and p21WAF1/CIP1. Increases in both epithelial cell proliferation and cell death, partially associated with p53 accumulation and high p21WAF1/CIP1 expression, are thus characteristic of active phase UC, as well as in remission of long-standing UC. Accelerated epithelial cell turnover caused by chronic inflammation and epithelial damage might predispose the mucosa to DNA damage, resulting in an elevated risk of mutation in line with dysplasia and carcinoma development in patients with UC.
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PMID:Enhanced epithelial cell turnover associated with p53 accumulation and high p21WAF1/CIP1 expression in ulcerative colitis. 1039 37

In patients with chronic ulcerative colitis (CUC), polypoid dysplastic lesions (PDLs) are morphologically similar to sporadic adenomas (SAs), but may be biologically distinct from them and are managed differently. p53 mutations have been shown to occur at an earlier phase in the progression of CUC-associated neoplasia when compared with sporadic colon carcinogenesis. In contrast, APC gene mutations are common and occur at an earlier stage in the development of SA. beta catenin is a cell membrane protein that accumulates in the nucleus of colon cancer cells in response to APC gene mutations. This study was performed to test the hypothesis that CUC-associated PDLs have a different molecular profile than do CUC-associated SAs and therefore may be distinguished on this basis. Mucosal biopsy specimens of 38 benign polypoid epithelial neoplasms (17 CUC-associated PDLs and 21 CUC-associated SAs) from 33 patients with CUC and 13 SAs from patients without CUC (controls) were immunohistochemically stained for p53 and beta catenin and graded as follows: 0 = no staining, 1+ = <50% of cells positive, and 2+ = > or =50% of cells positive. The results were correlated with the clinical and histologic features and compared between the two CUC-associated polyp subgroups. Overall, six (16%) polyps were p53-positive, of which five were CUC-associated PDLs (one 1+ and four 2+) and one was a CUC-associated SA (1+) (p = 0.05). Strong (2+) p53 positivity was detected, however, in only CUC-associated PDLs (4 of 5; 80%). Nine of 32 polyps evaluated for beta catenin were positive and included 1 (8%) of 12 CUC-associated PDLs and 8 (40%) of 20 CUC-associated SAs (p = 0.06). Two of the nine beta catenin polyps were strongly positive, and both were CUC-associated SAs. Non-CUC-associated (control) SAs were positive for p53 and beta catenin in 2 (15%) of 13 and 6 (46%) of 13 cases, but none in a strong (2+) fashion. No differences were observed in p53 or beta catenin staining, between CUC-associated and non-CUC-associated SAs. Neither p53 nor beta catenin expression correlated with any clinical or pathologic features, including size and degree of dysplasia of the polyps. CUC-associated PDLs and CUC-associated SAs may have a different molecular genotype. In patients with CUC, the combination of strong p53 expression and absent or weak beta catenin expression is evidence in favor of a CUC-associated PDL in diagnostically difficult lesions. Furthermore, CUC-associated and non-CUC-associated SAs have a similar P53 and beta catenin immunophenotype and thus provide evidence that they are pathogenetically related neoplasms regardless of the presence or absence of colitis.
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PMID:P53 and beta catenin expression in chronic ulcerative colitis--associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. 1043 67

Adenomas in areas involved by ulcerative colitis (UCA) are difficult to identify because of their morphological similarity to ulcerative colitis-associated dysplasia (UCD) and have an uncertain biology. Recently, a set of morphopathologic criteria were published for the diagnosis of UCA versus UCD. As a first step to analyze these criteria, we studied p53 and bcl-2 expression in groups of UCA and UCD along with a sporadic adenoma control group. Ninety lesions from UC areas (62 patients) were examined, including 24 UCA without high-grade dysplasia (HGD) and 66 UCD consisting of 43 polypoid and 23 flat dysplastic lesions (29 with HGD). Immunohistochemical p53 and bcl-2 expression were evaluated semiquantitatively. P53-positive cases were significantly less frequent in the UCA (4%) versus the UCD group (30%, P = .01) and the polypoid UCD subgroup (35%, P = .005). Moderate or strong bcl-2 expression was significantly more frequent in the UCA than in the UCD group (96% v 70%, P = .01) and in the UCA versus both polypoid and flat UCD subgroups. Comparison of UCA with low-grade dysplastic polypoid UCD cases alone showed a difference just below significance for p53 (P = .07). p53 and bcl-2 expression rates were very similar in the UCA group and the sporadic adenoma (n = 25) control group. These results show that UCA has phenotypic features more similar to sporadic adenomas than UCD and supports the concept that adenomas in UC have a biology different from UC-associated dysplasia.
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PMID:The differentiation of true adenomas from colitis-associated dysplasia in ulcerative colitis: a comparative immunohistochemical study. 1045 1

The purpose of this study was to determine whether point mutations and loss of the p53 gene take place in ulcerative colitis which is histologically negative for dysplasia. DNA was extracted from 13 frozen rectal or colon biopsies and blood samples. Ulcerative colitis was classified histologically as active (10 cases) and inactive (3 cases). Exons 5-8 were amplified by PCR, treated with exonuclease and shrimp alkaline phosphatase and sequenced by the dideoxy chain termination method with the Sequenase Version 2.0 DNA sequencing kit. PCR products of intron 6 and exon 4 were digested with MspI and AccII, respectively, for RFLP analysis. No p53 gene mutation was detected in these cases. The number of informative patients for loss of heterozygosity (LOH) at the p53 intron 6 was high, 11 out of 12 (92%), whereas no LOH was observed. LOH affecting p53 exon 4 was not detected in lesions from 5 of 12 patients (42%). In ulcerative colitis, tumor progression is similar to that in sporadic colon cancer, and other oncogenes and tumor suppressor genes are likely to be mutated before the p53 gene.
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PMID:Infrequent p53 gene alterations in ulcerative colitis. 1046 83

Patients with long-standing ulcerative colitis (UC) are at increased risk for colon cancer. These cancers are thought to arise from preexisting dysplasia in a field of abnormal cells that often exhibits aneuploidy and p53 abnormalities. Using dual color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosomes 8, 11, 17, and 18, we demonstrate that chromosomal instability (CIN) is present throughout the colon of UC patients with high-grade dysplasia or cancer. In rectal biopsies that were negative for dysplasia, abnormalities in chromosomal arms, especially losses, were most common, whereas centromere gains were most common in dysplasia and cancer. The frequency and type of abnormalities varied between the chromosomes examined; chromosome 8 was the least affected, and 17p loss was found to be an early and frequent event. Chromosomal arm instability showed 100% sensitivity and specificity for distinguishing control biopsies from histologically negative rectal biopsies from these UC patients, raising the possibility that a screen for CIN might detect the subset of UC patients who are at greatest risk for development of dysplasia and cancer. These results suggest that dysplasia and cancer in UC arise from a process of CIN that affects the entire colon; this may provide the mutator phenotype that predisposes to loss of tumor suppressor genes and evolution of cancer.
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PMID:Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. 1053 90

We report two cases affected by neoplasia after colectomy with ileo-rectal anastomosis (IRA) with a positive family history of colon cancer. Case 1, a 41-year-old ulcerative colitis (UC) patient, underwent IRA in 1977. In 1986, biopsies showed high-grade dysplasia. She underwent resection of the rectal stump in 1986. Submucosal invasive carcinoma was found in the surgical specimen. The immunohistological study demonstrated p53 protein overexpression in the neoplastic lesion. Her family history fulfilled the Amsterdam criteria of hereditary non-polyposis colorectal cancer (HNPCC). Case 2, a 47-year-old UC patient, underwent ascending colostomy in 1975 and the following year IRA. Endoscopic mucosal resection (EMR) for a sessile adenoma was performed in 1995 and subsequently polypectomy was performed for the residual tumor. Recurrent adenoma and dysplasia in another area were detected. The immunohistological study demonstrated p53 protein overexpression only in dysplasia. Renal cancer in the right kidney was detected. Resection of the rectal stump with ileal pouch-anal anastomosis (IAA), loop ileostomy and right nephrectomy were performed in 1998. Her mother and her mother's sister had been diagnosed with colon cancer. Only in the dysplastic lesion did we detect microsatellite instability at D5S644. Both cases with neoplasia had two relatives with colorectal carcinoma. In 33 cases with UC who had been followed up, 30 cases (96.8%) without neoplasia had no family history of colorectal carcinoma. These findings suggest that UC patients with a family history of colon cancer should be put under close surveillance. It should also be emphasized that IAA is the procedure of choice for UC patients with this particular condition.
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PMID:Ulcerative colitis patients with a family history of colorectal cancer should be subjected to close and careful surveillance. 1056 1

In order to evaluate the usefulness of p53 immunohistochemistry (IHC) in the diagnosis of ulcerative colitis-associated colorectal carcinoma (UCACRC), ordinary paraffin sections were examined in 61 cases with ulcerative colitis (UC) and 29 control cases without UC. Among the 61 cases with UC, 11 were complicated by carcinoma coexisting with dysplasia, three with dysplasia, and two cases with adenoma. There were a total of 38 dysplasias, including 33 low grade dysplasias (LGD) and five mixed low and high grade dysplasias (LGD + HGD). The results of p53 IHC were divided into diffuse, nested, scattered and sporadic patterns for 29 control cases. Diffuse and nested patterns were presumed to reflect mutant forms of p53 protein and were defined as overexpression of p53 protein. In non-neoplastic mucosa of UC, the frequency of p53 positive tubules was significantly higher in active phase (13.5-17.9%) than in resolving phase (3.9-6.5%) and in remission (0.7-2.4%), regardless of association with neoplasia. Eight of the 37 lesions of dysplasia (21. 6%) showed p53 overexpression: 12.5% in LGD and 80.0% in LGD + HGD. The rate of p53 overexpression was significantly higher in UCACRC (90.9%) than in non-neoplastic mucosa of UC (0%), LGD and sporadic colorectal carcinoma (54.5%), but it did not differ between UCACRC and LGD + HGD. Interestingly, the mucosa without dysplasia showed p53 overexpression in one case of UCACRC. The biopsy specimen taken 4 years before the diagnosis of carcinoma revealed p53 overexpression in another case with UCACRC. These results suggest that p53 abnormalities play an important role in UC-associated tumorigenesis in its relatively early phase. For the diagnosis of dysplasia and carcinoma in UC, p53 IHC seems to be useful.
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PMID:p53 immunohistochemistry of ulcerative colitis-associated with dysplasia and carcinoma. 1057 18

Ulcerative colitis(UC) is an ulcero inflammatory disorder of unknown etiology affecting only the mucosa and submucosa of colon and, with Crohn's disease, is included in the term idiopathic inflammatory bowel disease. The macroscopic and microscopic features vary according to the stage of the disease process, and an acute phase and a chronic or resolving phase can be recognized. The main differential diagnosis of UC is with colorectal Crohn's disease. The most feared long-term complication of UC is cancer. The progression of UC to carcinoma is closely associated with dysplasia arising in multiple sites. The dysplastic changes should be distinguished from the epithelial changes resulting from regenerative atypia, and the evaluation of these changes is difficult. P53 immunohistochemical staining is helpful in confirming the presence of dysplasia. Molecular events in colorectal carcinogenesis of UC may be somewhat different from those of so-called adenoma-carcinoma sequence.
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PMID:[Morphologic features of ulcerative colitis]. 1057 5


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