Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA replication errors (RERs) in repeated nucleotide sequences due to defective mismatch repair genes have been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC). We detected RER in 18 cases (13%) in a prospective series of 137 sporadic stage II and III (Dukes' B and C) colorectal carcinomas. The clinical and pathological features of the RER-positive cases differed from those without RER. The patients with RER-positive cancers tended to be somewhat younger (60 +/- 5 years, range 22-83, versus 66 +/- 1, range 27-90, P = 0.2 with unequal variances) and had a marked preponderance of tumors proximal to the splenic flexure (17/18, 94%, versus 41/119, 34%, P < 0.0001). Only two RER-positive patients (11%) had a family history of colorectal cancer. In comparison to the 41 RER-negative proximal colonic cancers, RER-positive cancers had more frequent exophytic growth (P = 0.04), large size (P = 0.03), poor differentiation (P = 0.0004), extracellular mucin production (P = 0.003) and Crohn's-like lymphoid reaction (P = 0.003), and a trend toward less frequent p53 gene product overexpression by immunohistochemistry (3/17, 18%, versus 18/41, 44%, P = 0.06). We conclude that a subset of sporadic colorectal carcinomas has unique biological features that may indicate inherited germline mutation, de novo germline mutation, or somatic mutations of the mismatch repair genes involved in HNPCC.
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PMID:Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. 1098 Jan 44

Physiologic overexpression of p53 protein may occur in the G1 stage of the cell cycle to slow down the cell cycle and allow DNA repair in stressed or injured cells. We questioned whether there is increased expression of p53 protein in acutely inflamed mucosa (AI) and regenerated mucosa (RM) in ulcerative colitis (UC) and Crohn's disease (CD). Formalin-fixed paraffin-embedded sections of resected bowels from eight patients with UC and 20 with CD were reviewed, and blocks were selected having areas defined as follows: AI = two high-power fields (HPFs) at the edge of an ulcer, or one HPF with an inflamed crypt in the center; RM = branched or irregular glands with only mild chronic inflammation. Blocks with normal mucosa were available in 20 cases. One case of CD also had dysplasia, adenoma, and invasive carcinoma. p53 was identified with PAb1801 antibody using a labeled avidin-biotin immunoperoxidase technique. In each defined area, the positive nuclei were counted and expressed as the number of positive nuclei per 10 HPFs. Data were analyzed statistically for comparisons within and between the diseases. In normal mucosa, only rare cells expressed p53 in two cases of CD. The mean frequency of positive nuclei was 2.24/10 HPFs in AI and 0.30/10 HPFs in RM in CD, and 7.63/10 HPFs in AI and 1.14/10 HPFs in RM in UC. Differences between the means for AI and RM were statistically significant in both UC and CD. Although not significant, the frequency of positive staining in both AI and RM was greater in UC as compared with CD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of p53 antigen in inflamed and regenerated mucosa in ulcerative colitis and Crohn's disease. 853

Protooncogenes are cell cycle-related genes that are involved in cell growth of proliferation. Alterations in the level of expression of these genes, or expression of aberrant gene productions, have been observed in tumors and precancerous conditions. To determine if expression of these genes is altered in patients with inflammatory bowel disease (IBD) --who are at risk for development of colon cancer--we assayed transcripts of 15 protooncogenes in colonic epithelial cells of IBD patients and controls. Nine of these genes (H-ras, c-myc, c-fos, c-jun, junB, N-myc, c-abl, c-yes, and p53) were expressed in epithelial cells, whereas two (RB1 and N-ras) were not. expression of four other genes (c-src, K-ras, c-raf, and c-myb) was observed, but the intensity of these bands was too low for densitometric analysis. The steady-state levels of transcripts of H-ras and five nuclear protooncogenes (c-myc, c-fos, c-jun, junB, and N-myc) were lower in epithelial cells from involved or uninvolved IBD samples than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. The level of c-fos mRNA was two- to threefold higher in involved than in uninvolved areas of the colons of two ulcerative colitis (UC) patients, but not in one Crohn's disease (CD) patient. Message abundance of c-abl transcripts was two- to threefold lower in UC epithelial cells than in either the CD or control samples. The steady-state level of c-yes-encoded mRNA was considerably higher in IBD patients resected for colon cancer than in patients resected for active chronic IBD or in controls. The level of p53 message was constant in these samples. Increased levels of c-fos mRNA in involved UC relative to uninvolved UC may be related to the disease process. Decreased expression of c-abl transcript in UC may be a diagnostic marker for UC and may be related to the rate of cell turnover in these diseases. Enhanced expression of c-yes in IBD patients with tumors compared to active chronic IBD and controls suggests that expression of this gene may be a marker for development of colon cancer in IBD.
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PMID:Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease. 867 85

In order to demonstrate the relationship between microsatellite instability and other types of genomic instability, a series of 56 sporadic colorectal carcinomas was investigated by flow cytometrical ploidy analysis, oligonucleotide fingerprinting, and microsatellite polymerase chain reaction (PCR). Stabilization of the p53 gene product was analysed by immunohistochemistry and proliferative activity was determined flow cytometrically and by silver staining of nucleolar organizer regions (AgNORs). Of the 56 carcinomas, 11 (19 per cent) exhibited microsatellite instability; 33 of the cases were aneuploid (59 per cent) and 29 (52 per cent) showed alterations of the oligonucleotide fingerprints. There was a significant correlation of microsatellite instability with localization of these tumours proximal to the splenic flexure, diploid DNA content, and less frequent p53 stabilization. A solid growth pattern, mucinous differentiation, and a Crohn's-like lymphoid infiltrate were also characteristic for those tumours. The results demonstrate for the first time a significantly lower proliferative activity in tumours with microsatellite instability. Data obtained from DNA flow cytometry or from oligonucleotide fingerprinting did not correlate with such tumour characteristics. It is proposed that the use of microsatellite PCR facilitates specifically the detection of a group of colorectal cancers which may differ in pathogenesis and perhaps prognosis.
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PMID:Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. 869 38

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

We report a rare case of Crohn disease accompanied by a small-bowel carcinoma that developed in a 54-year-old Japanese man. The ulcerating tumor, which histologically proved to be a poorly differentiated adenocarcinoma and dysplasia surrounding the carcinoma, was located in the diseased ileum. The Ki-67 immunoreactive epithelial cells were increased in regenerative mucosa as compared with values for normal mucosa. The Ki-67- and p53-positive cells were increased in dysplasia and carcinoma as compared with values for regenerative or normal mucosa. In contrast, the p21(WAF1/CIP1) immunoreactive cells were decreased in this order. Intense DCC (deleted in colorectal cancer) expression was constantly shown among normal, regenerative, dysplastic and cancerous tissues. No bcl-2 expression and c-Ki-ras mutations were apparent. In conclusion, enhanced epithelial cell proliferation, p53 overexpression, and decrease of p21(WAF1/CIP1) expression may predispose the small-bowel mucosa to dysplasia and carcinoma development in Crohn disease.
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PMID:A case of adenocarcinoma of the small intestine in a Japanese patient with Crohn disease: a report with immunohistochemical and oncogenic analyses. 1058 70

Colorectal cancer represents the major cause for excess morbidity and mortality by malignant disease in ulcerative colitis as well as in Crohn's disease. The risk for ulcerative colitis associated colorectal cancer is increased at least 2-fold compared to the normal population and colorectal cancer is observed in 5.5-13.5% of all patients with ulcerative colitis and 0.4-0.8% of patients with Crohn's disease. Established risk factors include long duration of the disease, large extent of the disease, low activity of the disease, young age at onset, presence of complicating primary sclerosing cholangitis or stenotic disease and possibly lack of adequate surveillance, inadequate pharmacological therapy, folate deficiency and non-smoking. Crohn's disease is associated with an increased risk of colorectal carcinoma in patients with long-standing disease, strictures and fistulae under the condition that the colon is involved, tumors of the small intestine may occur occasionally. Extracolonic malignancies are rare, with the exception of biliary tract cancer. Ulcerative colitis associated colorectal cancer typically can occur in the entire colon, is often multifocal and of undifferentiated histology. Stage distribution and prognosis of ulcerative colitis associated colorectal cancer appears to be similar to that of sporadic colorectal cancer with an overall survival of about 40% (15-65%) after 5 years with tumor stage at diagnosis being the most important predictive parameter for survival. Tumor markers helpful for the diagnosis of sporadic colorectal cancer fail to differentiate between inflammatory response and malignant transformation. In contrast the histologic evidence of dysplasia was shown to be a strong indicator of underlying carcinoma or developing malignant transformation. The presence of a surface projection termed dysplasia associated lesion or mass is highly indicative of underlying or associated cancer. While the routinely performed search for dysplasia is hampered by high interobserver variation the demonstration of DNA-aneuploidy or genetic changes which may confirm the ongoing malignant transformation has not yet become clinical routine. The genetic alterations found in ulcerative colitis associated colorectal cancer involve many of the same targets found in sporadic colorectal tumors and include multiple sites of allelic deletion, microsatellite instabilities, and mutations of APC, p53, Ki-ras as well as MSH2 and other genes. The progression of dysplasia to carcinoma is generally accompanied by an accumulation of these mutations and the similarities in the biology of colorectal cancer associated with ulcerative colitis and sporadic colorectal cancer appear to outweigh their difference. In regard to the management of dysplasia and cancer, the role of surveillance programs for the early detection of ulcerative colitis associated colorectal cancer at a curable stage is still under debate. Although these programs failed at tumor prevention and lethal carcinomas are still found inadvertently in patients under surveillance, the majority of surveillance programs could reduce mortality by detecting more cancers at a still curable stage. Current recommendations for surveillance include, therefore, biennial colonoscopy with extensive biopsies after 8-10 years of total colitis or after 15-20 years of left-sided colitis. In the presence of cancer or unequivocal high-grade dysplasia and/or dysplasia associated lesion or mass proctocolectomy is considered adequate. The evidence of low-grade dysplasia should be confirmed before proctocolectomy is considered.
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PMID:Chronic inflammatory bowel disease and cancer. 1069 May 86

Recent studies have demonstrated that angiogenesis and suppressed cell-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease.
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PMID:The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. 1074 Dec 73

A case of adenocarcinoma of the rectum in a 41-year-old woman, in association with Crohn's disease is presented. The patient had suffered diarrhea and constipation, and Crohn's disease was suspected. Although the endoscopy did not reveal the presence of any tumors, biopsy specimens demonstrated adenocarcinoma. A Miles' operation was performed. The adenocarcinoma was composed of various grades of atypia and had invaded the non-peritonealized perirectal tissues. The infiltration of lymphocytes and plasma cells was moderate at the perimeter of the carcinoma and mild in the distant regions. Epithelioid cell granulomas were found. The p53 labeling index (LI) increased with the grade of atypia over the entire length of the carcinomatous gland. In carcinomas with high grade atypia, the p53 LI was high in both the upper and the lower halves of the gland. In carcinomas with low or moderate grade atypia however, the p53 LI was high in the lower half and low in the upper half of the gland. The Ki-67 LI over the entire gland was higher in carcinomas with high grade atypia than in carcinomas with low or moderate grade atypia.
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PMID:Adenocarcinoma of the rectum with various grades of atypia in association with Crohn's disease: a case report and immunohistochemistry of p53 and Ki-67. 1084 18

Patients with Crohn's disease are at increased risk of developing intestinal adenocarcinoma. Dysplasia is both a marker and a precursor of adenocarcinoma in this setting. In a review of our cases of Crohn's-related adenocarcinoma, we noted a peculiar hyperplastic-like mucosal change (HPC) in mucosa both adjacent to and distant from the adenocarcinoma in some cases. However, the significance of this change is unknown. We evaluated 30 cases of Crohn's-related adenocarcinoma and 30 age- and site-matched resection specimens with Crohn's disease without adenocarcinoma to determine the prevalence of this mucosal alteration in these groups. HPC was recognized by a diffuse expanse of flat mucosa with an architecture resembling that seen in colorectal hyperplastic polyps and composed of cells with cytologically bland basal nuclei and apical cytoplasmic mucin distention. The relationship of the HPC to the adenocarcinoma was noted in the Crohn's-related adenocarcinoma cases. An immunohistochemical stain for p53 (antibody DO7) was performed on all cases with HPC in both groups. HPC was identified in 10 of 30 (33%) cases of Crohn's-related adenocarcinoma compared with 3 of 30 (10%) cases in the control group (P = .03). In the 10 cases of Crohn's-related adenocarcinoma with HPC, this alteration was found adjacent to the adenocarcinoma in 3 cases, distant to the adenocarcinoma in 5 cases, and both adjacent to and distal from the adenocarcinoma in 2 cases. In two specimens, HPC was seen immediately adjacent to adenocarcinoma in the absence of adjacent dysplasia. p53 immunoreactivity was noted in HPC in 5 of 10 (50%) Crohn's-related adenocarcinomas. In contrast, p53 immunoreactivity was not seen in HPC in the three control cases with this mucosal alteration. In conclusion, HPC is found significantly more commonly in mucosa both adjacent to and distant from Crohn's-related adenocarcinoma when compared with age- and site-matched controls. In addition, p53 immunoreactivity is more commonly seen in HPC in cases of Crohn's-related adenocarcinoma compared with controls. These data suggest that this mucosal alteration may, in some cases, represent an unusual form of dysplasia in this setting.
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PMID:Hyperplastic-like mucosal change in Crohn's disease: an unusual form of dysplasia? 1091 40


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