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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which were either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or unaffected by TGF beta 1, indicating that a switch in response to TGF beta 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. The current study shows that while the poorly differentiated, TGF beta 1-stimulated sublines are most tumorigenic, all the sublines have the same spectrum of mutations: truncating mutations in both APC (adenomatous polyposis coli) alleles, no activated ras genes, mutated and thus overexpressed p53, and very low expression of DCC compared to normal colon cells. Genes other than the four already implicated in colon carcinoma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.
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PMID:The capacity for growth stimulation by TGF beta 1 seen only in advanced colon cancers cannot be ascribed to mutations in APC, DCC, p53 or ras. 797 Jul 29

Our study was undertaken to determine the prognostic significance of several common genetic alterations observed in colorectal carcinomas. We have previously analysed loss of heterozygosity of the MCC, APC, p53 and DCC tumour suppressor gene loci as well as p53 gene mutations and protein over-expression in a series of 100 Dukes' stage B and C colorectal tumours obtained at surgery. To extend our observations of alterations that may occur in these tumours, mutations to the c-Ki-ras oncogene and APC tumour suppressor gene were detected by PCR single-strand conformation polymorphism analysis. Short-term follow-up revealed no significant association between overall patient survival and any single, or combination of, genetic alteration(s). Surprisingly, patients whose tumours showed evidence of p53 protein over-expression/accumulation by immunocytochemistry (ICC) had a significantly better prognosis (p = 0.039) than those whose tumours had no p53 ICC reactivity.
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PMID:The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short-term prognostic indicators of survival. 798 12

The B6C3F1 mouse is used worldwide to gauge the carcinogenic hazard posed by chemicals to humans. An assessment of the ability of this rodent model to predict human neoplasia requires an evaluation of similarities and differences in the genetics of tumor formation between these two species. We examined 142 spontaneous and chemically-induced liver tumors isolated from the B6C3F1 mouse for losses of heterozygosity (LOH) at 78 polymorphic loci and compared these results to genetic changes known to occur in human hepatocellular carcinoma. Approximately a third of the 142 mouse tumors exhibited LOH, suggesting that tumor suppressor gene inactivation may be involved in the formation of mouse liver tumors. Most of the LOH observed was restricted to seven chromosome sites and most of the tumors that underwent LOH lost alleles from only one of those seven sites. The relatively few losses seen in these mouse tumors distinguished them from clinical stage human tumors in that, in the mouse tumors, interstitial deletions appeared more frequently than losses of whole chromosomes. Only four mouse tumors lost a whole chromosome. LOH occurred at loci of the mouse genome syntenic to areas of the human genome known to harbor the Wilms', retinoblastoma, APC, MCC and DCC tumor suppressor genes; these genes have never been associated with hepatocellular carcinomas. Losses observed on chromosomes 5 and 8 (syntenic to human chromosomes 4 and 16) suggest tumor suppressor genes that are common to hepatocellular carcinomas from both species, while losses on chromosome 9 suggest involvement of a previously unidentified tumor suppressor gene.
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PMID:Loss of heterozygosity in spontaneous and chemically induced tumors of the B6C3F1 mouse. 805 44

We used Southern blot analysis and polymerase chain reaction-based techniques to examine deletions of tumour suppressor gene loci in 91 primary colorectal tumours. The tumour suppressor genes studied were MCC and APC on chromosome 5q, p53 on chromosome 17p, DCC on chromosome 18q, and the putative suppressor gene nm23-H1 on chromosome 17q. The most frequent allelic loss observed was in chromosome 17p with 76% (68/89) of informative tumours showing loss of heterozygosity at this locus, followed by 34% (19/55) for DCC, 31% (12/39) for MCC, 17% (9/53) for APC and 16% (3/19) for nm23. No significant differences in the frequency of these suppressor gene allelic losses were observed between Dukes B and C stage adenocarcinomas.
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PMID:Loss of heterozygosity of tumour suppressor gene loci in human colorectal carcinoma. 808 Jun 84

Genetic alterations of several oncogenes and tumor suppressor genes are associated with human colorectal carcinogenesis. Especially in mutations, the K-ras, p53, APC and DCC gene frequently occurred, and these gene alterations seem to have important roles in colorectal carcinogenesis. We investigated 28 human colon cancer specimens obtained from surgery and five human colon cancer cell lines by PCR-SSCP assay, PCR-OSH assay, RT-PCR or sequencing method. Forty percent of cancers from surgical specimens had Ki-ras 2 (codon 12/13), p53 (Exon 5-8), APC (MCR) gene mutations, and fifty-seven percent of them had lower expression of DCC gene that of normal matched colon mucosa of the same patient. G to A transition was the most frequent in K-ras mutational spectrum in this case; 25% of patients had both k-ras and p53 gene point mutations. Form the results, we concluded that it in colorectal carcinogenesis for both K-ras and p53 gene point mutations might not necessary occur.
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PMID:[Genetic alterations of human colorectal cancer]. 810 90

We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.
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PMID:A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene. 813 40

Genetic and environmental aspects play an important role in the development of colorectal cancer. However, the common molecular alteration in both hereditary and sporadic colon cancer is localized in the APC gene. the APC gene maps in the long arm of chromosome 5 and was discovered in patients with familial adenomatous polyposis (FAP). The search for the APC gene led to the identification of restriction fragment length polymorphisms (RFLPs) in FAP patients. Using these RFLPs in relatives of FAP patients it is possible to make the presymptomatic and prenatal diagnosis. The FAP syndrome is an interesting model of carcinogenesis in vivo. Thus the different stages involved in the FAP syndrome which include hyperproliferative epithelium, adenoma, adenocarcinoma and metastases, have allowed the analysis of molecular alterations in oncogenes and tumor suppressor genes. The APC gene alteration if not inherited, occurs as the earliest molecular alteration in the development of colorectal cancer whereas structural alterations of the genes myc, ras, p53, MCC and DCC are considered to be late events. All these investigations have lead to 1) a better understanding of the ethiology of cancer and 2) early diagnosis of colorectal cancer in both the hereditary and sporadic forms of the disease.
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PMID:[Molecular genetics of colorectal cancer and carcinogenesis]. 813 31

In previous studies, we have shown that allelic loss on chromosome 17p, on which the p53 gene is located, is very frequent, and loss-of-function mutations of the p53 gene are closely associated with the tumorigenesis of esophageal cancer. In this study, we performed allelotype analysis to investigate whether other tumor suppressor genes are also involved in esophageal cancer. Using 55 polymorphic DNA markers covering every autosomal arm except 13p, 21p, and 22p, restriction fragment length polymorphism analysis was performed on 36 esophageal squamous cell carcinomas (ESCs) and their adjacent normal tissue samples. Frequent loss of heterozygosity (LOH) of > 30% of the informative cases was observed on chromosomes 3p (41.1%), 5q (52.6%), 6p (30.4%), 8p (33.3%), 9p (35.7%), 9q (30.8%), 11p (32.4%), 13q (52.7%), 17p (55.2%), 17q (33.3%), 18q (45.7%), and 19q (30.4%). Among these, LOH on 5q, 13q, 17p, and 18q was previously reported in ESC and is considered to involve the APC, RB, p53, and DCC genes, respectively. However, our deletion analysis of chromosome 18q revealed that the region commonly lost did not include the DCC locus, suggesting that a possible tumor suppressor gene on 18q other than the DCC gene is involved in ESC. We screened 60 primary ESC tumors and 20 cultured ESC cell lines for the mutation of the APC gene within a mutation cluster region in exon 15, where the "hot spot" of somatic mutation for colorectal and pancreatic cancers is thought to be. We could not find any mutation despite the high frequency of LOH on chromosome 5q. We also analyzed the relationship between the clinicopathological data and the allelic loss and found that LOH on chromosomes 6p and 13q was associated with poor prognosis.
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PMID:Allelotype analysis of esophageal squamous cell carcinoma. 818 88

Colorectal carcinogenesis is a multistep process that is accompanied by accumulation of changes in proto-oncogenes and tumor-suppressor genes. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes, as well as other genomic alterations appear at characteristic stages of tumor development and are observed in most neoplasms. However, consideration of each of these abnormalities leaves many unanswered questions. The striking data on recurrent amplification of the RB tumor-suppressor gene as well as suppressive activities of protein kinase C and activated RAS genes, at least in some colon carcinoma cell lines, suggest the unusual effects of some signalling pathways in colonic epithelial cells. The results obtained to date indicate that distinct sets of genetic changes may underlie the development of colorectal tumors.
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PMID:Genetic events responsible for colorectal tumorigenesis: achievements and challenges. 824 74

Thirty-four primary, untreated sporadic breast cancers were examined for loss of heterozygosity (LOH) at tumour suppressor loci involved in colorectal cancer: APC/MCC at 5q21 and DCC at 18q21. LOH was identified in 28% informative patients at 5q21 and 31% at 18q21. LOH at 5q21 and 18q21 was compared with allele loss at 17p13 and concurrent LOH at two or more of the loci was noted in 24% of tumours. Expression of a 12 kb DCC mRNA was demonstrated in 14/34 (42%) of the cancers and in all five tumours with LOH at the DCC locus there was an additional 11 kb DCC mRNA. Abnormalities of three loci involved in colorectal cancer (5q21, 17p13 and 18q21) therefore also occur in sporadic breast cancer. The accumulation of such genetic abnormalities may confer a growth advantage important in the development of breast cancer.
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PMID:Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. 831 22


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