Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity occurring on various chromosomes has been described in the majority of human tumors. The targets of frequent or consistent subchromosomal deletions are believed to be tumor suppressor genes. We examined 72 esophageal tumors (46 squamous cell carcinomas and 26 adenocarcinomas) for loss of heterozygosity at the p53, Rb, APC, MCC, and DCC loci. Inclusion of these tumor suppressor genes in the allelic deletions was directly ascertained by performing polymerase chain reaction at polymorphic sites within the genes. Loss of heterozygosity occurred in 55% of informative cases at p53, in 48% of informative cases at Rb, in 66% at APC, in 63% at MCC, and in 24% at DCC. Ninety-three % of tumors informative at all loci (fully informative) lost heterozygosity of at least one locus. A high percentage of fully informative tumors (71%) also lost heterozygosity at more than one locus. There were no significant differences among histological types in the prevalence of loss of heterozygosity at any locus. There were correlations of losses involving MCC versus DCC, Rb, and p53. These data suggest that (a) allelic deletions including these tumor suppressor genes are important in the formation and/or progression of most esophageal cancers; (b) allelic deletions involving MCC may not occur independently of deletions involving other tumor suppressor genes; and (c) the accumulation of multiple allelic deletions involving specific tumor suppressor genes may be important in most esophageal tumorigenesis or tumor evolution.
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PMID:Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. 142 99

Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate to bring about the neoplastic phenotype. Colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the inactivation of several tumor suppressor genes. We have found frequent allelic deletions of specific portions of chromosomes 5, 17, and 18 which presumably harbor suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is frequently mutated not only in colon cancer but in several other tumor types as well. Candidate suppressor genes have also recently been identified on chromosomes 18 and 5. The DCC gene on chromosome 18q encodes a protein with significant sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. Alterations of this gene may interfere with normal cell growth and differentiation by disrupting cell-cell or cell-substrate interactions. Two genes (MCC and APC) on chromosome 5q have also recently been identified and partially cloned. These genes are located in a region tightly linked to familial adenomatous polyposis (FAP). While MCC mutations have been found only in sporadic colon tumors, APC mutations have been identified in sporadic tumors as well as the germline of patients with FAP. Studies are currently in progress to increase our understanding of how alterations of these genes affect colorectal tumor cell growth.
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PMID:Suppressor gene alterations in the colorectal adenoma-carcinoma sequence. 146 93

Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.
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PMID:APC mutations occur early during colorectal tumorigenesis. 152 64

Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.
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PMID:Identification of FAP locus genes from chromosome 5q21. 165 62

Familial adenomatous polyposis (FAP), which includes familial polyposis coli (FPC) and the Gardner syndrome (GS), is a genetically determined premalignant disease of the colon inherited by a locus (APC) mapping within 5q15-q22. To elucidate the role of 5q loss in FAP tumorigenesis, we analysed 51 colorectal tumors and seven desmoids from 19 cases of FPC and five GS patients, as well as 15 sporadic colon cancers. RFLP analysis revealed a high incidence of allelic deletion in hereditary colon cancers as well as in sporadic colon cancers with a peak at the APC locus. APC loss resulted primarily from interstitial deletion or mitotic recombination. Combined tumor and pedigree analysis in a GS family revealed loss of normal 5q alleles in three tumors, including a desmoid tumor, which suggests the involvement of hemizygosity or homozygosity of the defective APC gene in colon carcinogenesis and, possibly, in extracolonic neoplasms associated with FAP.
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PMID:Molecular nature of chromosome 5q loss in colorectal tumors and desmoids from patients with familial adenomatous polyposis. 217 53

To investigate genetic features of esophageal cancer, we have examined 93 squamous cell carcinomas of the esophagus for loss of heterozygosity (LOH), using 41 restriction fragment length polymorphism (RFLP) markers representing all autosomal chromosomes. Allelic losses at frequencies of at least 30% were observed at loci on chromosomal arms 3p (35%), 3q (30%), 5q (36%), 9p (57%), 9q (60%), 10p (33%), 13q (43%), 17p (62%), 17q (46%), 18q (38%), 19q (32%), and 21q (37%). These results suggest that several putative tumor suppressor genes, in addition to the cyclin D and TP53 genes that are sometimes mutated in esophageal carcinomas, may be associated with development and/or progression of esophageal cancer. By a comparison of LOH on each chromosomal arm with clinicopathological parameters, we have found a significant correlation between LOH on 19q and regional lymph node metastases. Interestingly, the frequency of LOH on 17q was significantly higher in tumors in female patients (12 of 14 cases) than in those in male patients (20 of 56 cases) (P = 0.0009 by Fisher's exact test). Furthermore, we examined for mutations of the APC gene on chromosome arm 5q. Screening of nearly one third of the APC coding region, including the MCR (mutation cluster region), revealed no alterations. Therefore, although allelic loss at the APC locus is frequent in squamous cell carcinomas of the esophagus, it is likely that a gene on 5q other than APC is involved in esophageal tumorigenesis.
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PMID:Allelotype study of esophageal carcinoma. 752 40

Min (multiple intestinal neoplasia) is a mutant allele of the murine Apc (adenomatous polyposis coli) locus, encoding a nonsense mutation at codon 850. Like humans with germline mutations in APC, Min/+ mice are predisposed to intestinal adenoma formation. The number of adenomas is influenced by modifier loci carried by different inbred strains. One modifier locus, Mom-1 (modifier of Min-1), maps to distal chromosome 4. Intestinal tumours from both B6 (C57BL/6J) and hybrid Min/+ mice show extensive loss of the wild-type allele at Apc. B6 Min/+ female mice are predisposed to spontaneous mammary tumours. The incidence of both intestinal and mammary tumours can be increased in an age-specific manner by treatment with ethylnitrosourea (ENU). Min mice provide a good animal model for studying the role of Apc and interacting genes in the initiation and progression of intestinal and mammary tumorigenesis.
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PMID:ApcMin: a mouse model for intestinal and mammary tumorigenesis. 757 92

One hallmark of malignant potential is dysplasia, the disruption of normal morphology. While it is generally recognized that cancer is the result of a series of genetic changes, the relationship of these alterations and their timing to the advent of dysplasia remains obscure. To address this issue, 54 small benign colorectal lesions of various malignant potential were analyzed for APC and K-RAS mutations, two alterations which have been implicated in the early stages of colorectal tumorigenesis. APC mutations were closely associated with dysplasia. In contrast, K-RAS mutations were found to be remarkably common in small nondysplastic lesions which apparently have a limited potential to progress to larger tumors. These results provide evidence that the nature and order of genetic changes can have a specific impact on both tumor morphology (e.g., dysplasia) and the likelihood of tumor progression.
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PMID:Molecular determinants of dysplasia in colorectal lesions. 792 89

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomatous polyps, the precursors to colorectal cancer. APC and ras gene mutations have been shown to be important early molecular events in the development of colorectal neoplasms. The objective of this study was to establish the nature and frequency of these two genetic alterations in ACF harvested from human colorectal resection specimens. One hundred and fifty-four ACF comprised of between 1 and 56 crypts were harvested from the grossly normal mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colons were screened for the presence of K-ras codon 12 mutations with a polymerase chain reaction/restriction enzyme-based method. The APC gene mutation cluster region was screened in 65 ACF from 20 colons using a polymerase chain reaction/single strand conformation polymorphism technique. Putative mutations were confirmed by direct sequencing. K-ras codon 12 mutations were identified in 13% (16 of 125) of ACF. We also identified APC mutations in 4.6% (3 of 65) of ACF. The results of this study demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precursor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.
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PMID:Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. 792 90

Several epidemiological studies have demonstrated an association between familial adenomatous polyposis coli (FAP) and thyroid neoplasms. Predisposition to FAP is conferred by mutations in the APC gene, located on chromosome 5q21. Somatic mutations of APC are also observed in about 60% of sporadic colorectal adenomas and carcinomas, suggesting that disruption of this putative tumor suppressor gene may play a role in both familial as well as acquired colorectal tumorigenesis. The APC gene is expressed in normal human thyroid, thyroid adenomas, and differentiated carcinoma tissues as well as in four clonal human thyroid carcinoma cell lines, as demonstrated by reverse transcriptase-polymerase chain reaction of a 388-base APC messenger ribonucleic acid fragment spanning exons 14 and 15, followed by hybridization to an exon 15-specific complementary DNA probe. Eighty human thyroid neoplasms were examined for loss of heterozygosity of the APC locus, using primers flanking a hypervariable dinucleotide (CA) repeat (CB26) immediately adjacent to the APC gene. Of 71% informative samples, 2 showed allelic loss: a follicular adenoma (FA) and a nodule from a multinodular goiter (MNG). The DNA of 83 benign and malignant thyroid neoplasms and 4 thyroid carcinoma cell lines was examined for mutations within a 1200-basepair stretch of exon 15 by single strand conformation polymorphism. Five sets of overlapping primers were used for PCR. The anaplastic thyroid carcinoma cell line (ARO) had 1 APC allele with an adenine insertion at codon 1556 (ACTA to AACTA), leading to a premature stop codon at 1558. An anaplastic carcinoma had a mutation of codon 1346 (TCA-CCA; Ser to Pro). In summary, the APC gene is expressed in normal and neoplastic human thyroid tissue and is a target for inactivating mutations in some thyroid tumors.
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PMID:Mutations of the adenomatous polyposis coli gene in sporadic thyroid neoplasms. 796 23


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