Allelic Loss in Colorectal Carcinoma

Kern, Scott E.; Fearon, Eric R.; Tersmette, Kasper W. F.; Enterline, John P.; Leppert, M.; Nakamura, Yusuke; White, Ray; Vogelstein, Bert; Hamilton, Stanley R.

doi:10.1001/jama.1989.03420210047014

Cited by 271 publications

(54 citation statements)

References 33 publications

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“…In sporadic colorectal cancers, loss of APC function in targeting ␤-catenin for its degradation is thought to account for most of the alterations in ␤-catenin expression (4, 7, 29 -31). APC mutation and loss of heterozygosity on 5q are frequent and early events in sporadic colorectal carcinogenesis (19,(32)(33)(34)(35)(36)(37)(38). Loss of APC expression as detected by immunohistochemistry or Western blot analysis is seen in 50 to 80% of sporadic colorectal tumors (39,40).…”

Section: Discussionmentioning

confidence: 99%

Altered Distribution of β-Catenin, and Its Binding Proteins E-Cadherin and APC, in Ulcerative Colitis–Related Colorectal Cancers

et al. 2001

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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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Section: Discussionmentioning

confidence: 99%

Altered Distribution of β-Catenin, and Its Binding Proteins E-Cadherin and APC, in Ulcerative Colitis–Related Colorectal Cancers

et al. 2001

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“…These mutations were found to arise predominantly during the conversion of benign adenoma to invasive adenocarcinoma, and the highest percentage was found in late-stage tumours (Fearon and Vogelstein, 1990;Kikuchi-Yanoshita et al, 1992;Kaklamanis et al, 1993). Deletions of the short arm of chromosome 17p, which harbours the p53 gene, and point mutations within the p53 gene (as detected by sequence analysis) were found to be associated with vascular invasion (lino et al, 1994), distant metastases (Kern et al, 1989;Ookawa et al, 1993;Kastrinakis et al, 1995) and shorter survival (Laurent-Puig et al, 1992;Offerhaus et al, 1992;Hamelin et al, 1994;Pricolo et al, 1996).…”

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Immunohistochemical detection of p53 and Bcl-2 in colorectal carcinoma: no evidence for prognostic significance

Tollenaar

Krieken²,

Slooten³

et al. 1998

Br J Cancer

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Summary To evaluate the prognostic significance of immunohistochemically detected p53 and Bcl-2 proteins in colorectal cancer, tissue sections from 238 paraffin-embedded colorectal carcinomas were immunostained for p53 (MAb DO-7 and CM-1 antiserum) and Bcl-2 (MAb Bcl-2:124). Staining patterns were assessed semiquantitatively and correlated with each other and with sex, age, tumour site, Dukes' classification, tumour differentiation, mucinous characteristics, lymphocyte and eosinophilic granulocyte infiltration, and patient survival. In our series, 35% of carcinomas showed no nuclear staining and 34% (DO-7) to 40% (CM-1) showed staining in over 30% of tumour cell nuclei. A majority of carcinomas that had been immunostained with CM-1 showed cytoplasmic staining, but this was not observed with DO-7. With respect to Bcl-2, 51% of tumours were completely negative, 32% displayed weak and 15% moderate staining; only 3% showed strong positive staining. No evidence was found for reciprocity between Bcl-2 expression and nuclear p53 accumulation. From 13 cases containing tumour-associated adenoma, four were Bcl-2 negative in premalignant and malignant cells, in another four cases these cells showed similar staining intensities and in the remaining cases only the malignant colorectal cells were Bcl-2 negative. Therefore, our data indicate that Bcl-2 is dispensable in the progression towards carcinoma. Except for an association between nuclear p53 accumulation and mucinous tumours (P = 0.01), no significant correlation was found between the clinicopathological parameters mentioned above and immunostaining pattern of (nuclear or cytoplasmic) p53 or Bcl-2.Keywords: colorectal neoplasm; p53; Bcl-2; immunohistochemistry; prognosis At present, prognostication for colorectal cancer is based mainly on tumour stage, but, because marked differences in clinical outcome occur within each stage, there is an obvious need for better prognostic markers. Ideally, these markers should predict the chance that the tumour has disseminated at the time of primary surgery, thereby facilitating selection of subgroups of patients who might benefit from adjuvant chemotherapy and radiation therapy. For this purpose we selected a population of patients who underwent a curative resection without adjuvant chemotherapy and for whom post-operative follow-up was available.In normal colorectal mucosa there exists a stringently controlled balance between cell proliferation and cell death, and it has been hypothesized that a reduced capacity to undergo apoptotic cell death could be an important step in the development of neoplasia. (Bedi et al, 1995). Both the product of the tumour suppressor gene p53 and the products of the bcl-2 gene family are involved in regulation of cell proliferation and apoptosis, and alterations in these genes are related to oncogenesis and disease progression.Loss of p53 function has been strongly linked to development of malignancy (Hollstein et al, 1991) -about 70% of colorectal cancers were shown to bear p53 mutations and a simila...

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“…Genetic alterations accumulate during tumor progression and appear as a consequence of the instabilization of the genome. In many cases, the type and level of genomic damage has been associated to molecular and clinical parameters and its application as prognostic factor has been also propounded (Kokal et al, 1986;Kern et al, 1989;Arribas et al, 1997). Malignant transformation of the cell is also accompanied by aberrant expression of multiple genes.…”

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confidence: 99%

Overall deregulation in gene expression as a novel indicator of tumor aggressiveness in colorectal cancer

et al. 1999

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Allelic Loss in Colorectal Carcinoma

Cited by 271 publications

References 33 publications

Altered Distribution of β-Catenin, and Its Binding Proteins E-Cadherin and APC, in Ulcerative Colitis–Related Colorectal Cancers

Altered Distribution of β-Catenin, and Its Binding Proteins E-Cadherin and APC, in Ulcerative Colitis–Related Colorectal Cancers

Immunohistochemical detection of p53 and Bcl-2 in colorectal carcinoma: no evidence for prognostic significance

Overall deregulation in gene expression as a novel indicator of tumor aggressiveness in colorectal cancer

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