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

Cell fusion experiments performed by Harris et al. informed that tumor suppressor genes are inactivated in malignant cells. Inactivation of tumor suppressor genes induced by genetic alteration such as point mutation and deletion leads to disturbance in the control of cell proliferation resulting in deregulated growth of normal cells. Recently, many challenges of scientists including clinicians trying to direct the studies of tumor suppressors toward cancer therapy have been stimulated. For that purpose, it is important to understand the molecular mechanism in which change of normal phenotypes into tumor take place. In this review, recent topics on tumor suppressors such as Rb, p53, Wt1, APC, NF1, s-Myc and H19 are included to discuss their significance and function.
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PMID:[Tumor suppressor genes]. 785 29

We report here the use of multiplex fluorescent polymerase chain reaction (PCR) for quantitative allele loss detection using microsatellites with 2-5 base pair repeat motifs. Allele loss of APC, DCC, p53 and RB1 in colorectal tumours has been reported previously using a variety of methods. However, not all workers used intragenic markers. We have used microsatellite polymorphisms which map within, or are closely linked to, these tumour-suppressor gene loci in order to determine whether these loci are indeed the targets for alteration in colorectal cancer. In addition, we have assayed two other tumour-suppressor genes, WT1 and NF1, to see whether they play a role in colorectal carcinogenesis. The putative metastasis-suppressor gene, NM23, was also investigated since there have been conflicting reports about its involvement in colorectal carcinogenesis. Allele loss was detected at the DCC (29%), p53 (66%), RB1 (50%) and NF1 (14%) loci and in the APC/MCC region (50%), but not at the WT1 or NM23 loci. These rapid, and mostly gene-specific, fluorescent multiplex PCR assays for allele loss detection could be modified to devise a single molecular diagnostic test for the important lesions in colorectal cancer.
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PMID:Frequency of allele loss of DCC, p53, RBI, WT1, NF1, NM23 and APC/MCC in colorectal cancer assayed by fluorescent multiplex polymerase chain reaction. 794 85

The study of the genetic alterations of tumor suppressor genes and protooncogenes in solid tumors has greatly increased our understanding of cancer biology. These findings have extended epidemiologic associations of carcinogens with certain tumors. Further analysis of patterns of genetic changes may implicate carcinogenic substances in cases where epidemiology has not been able to do so. Identification of germline mutations in p53, APC, and NF1 has provided improved diagnosis and presymptomatic screening in cancer kindreds. The identification of additional alterations in tumor suppressor genes may further improve the ability to predict inherent cancer risk. Screening strategies based on detection of genetic abnormalities of preinvasive cancerous lesions, such as mutant ras in colonic polyps, may improve early diagnosis. Finally, strategies to replace lost tumor suppressor function may provide a future therapeutic modality.
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PMID:Genetic mechanisms of solid tumor oncogenesis. 814 Sep 69

Inactivation of antioncogenes result in the generation of tumor cells. Recent progress in molecular biology of antioncogenes enabled us to study the function of the products of RB, WT, p53, NF1, DCC, APC and MCC genes. Analyses of the function of these proteins will give us an insight into the mechanisms of cell transformation.
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PMID:[Functions of antioncogene products]. 834 43

Identification of inherited cancer-predisposing genes offers opportunities for cancer prevention. Inherited susceptibility genes have been identified, primarily through studies of unusual cancer cases and families but also through general population studies. Examples include the RB1 gene for retinoblastoma; the WT1 gene for Wilms' tumor; germline p53 mutations in families with the Li-Fraumeni syndrome; the NF1 and NF2 genes for neuroblastomatosis, types 1 and 2; the VHL gene for renal cancer and other tumors associated with Von Hippel-Lindau disease; the APC gene for adenomatous polyposis coli; the BRCA1 gene for hereditary breast and ovarian cancer; and the mismatch repair genes for colon and other common cancers. For some cancers, identification of gene carriers might be beneficial for targeting screening and chemopreventive interventions. On the other hand, predisposition testing for cancer has the potential for harm from loss of insurability and employability, psychological distress, social stigmatization and other adverse effects. Research is needed to identify predisposition testing procedures that maximize benefits while minimizing harm to subjects. Chemoprevention trials in genetically susceptible populations offer the prospect of finding effective methods of reducing future cancer risk.
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PMID:Identification and management of inherited cancer susceptibility. 874 2

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.
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PMID:Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. 882 21

Recent knowledge about biological role of tumor suppressor genes and their products: RB1, p53, WT1, DCC, APC/FAP, NF1, NF2, VHL, MCC and MTS1 is presented. The main approaches of these agents as physiological regulators of cell growth and proliferation are discussed. Views on the tumor suppressor genes involvement in the development of inherited and sporadic forms of cancer have been reviewed.
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PMID:[Antioncogenes--tumor suppression genes]. 933 80

Neurofibromatosis type 1 patients with a submicroscopic deletion spanning the NF1 tumor suppressor gene are remarkable for an early age at onset of cutaneous neurofibromas, suggesting the deletion of an additional locus that potentiates neurofibromagenesis. Construction of a 3.5 Mb BAC/PAC/YAC contig at chromosome 17q11.2 and analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb in length. The deletions encompassed the entire 350 kb NF1 gene, three additional genes, one pseudogene and 16 expressed sequence tags (ESTs). In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, termed NF1REPs. These REPs, or clusters of paralogous loci, are 15-100 kb and harbor at least four ESTs and an expressed SH3GL pseudogene. The remaining three patients had at least one breakpoint outside an NF1REP element; one had a smaller deletion thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data show that the likely mechanism of NF1 microdeletion is homologous recombination between NF1REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements reported here, NF1REP-mediated somatic recombination could be an important mechanism for the loss of heterozygosity at NF1 in tumors of NF1 patients.
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PMID:NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. 1058 76

Large deletions of the NF1 locus occur in 5 to 10% of patients with neurofibromatosis and are commonly associated with specific additional abnormalities characterized by mental retardation, dysmorphic features, and intellectual impairment. To characterize the extent of codeleted genes we constructed a long-range physical BAC/PAC map around the NF1 locus between D17S117 and D17S57 and determined the deletion boundaries in seven unrelated patients. Surprisingly, the proximal and distal breakpoints in five of seven patients fall at almost identical positions, resulting in the loss of at least 11 functional genes. Five of six patients investigated showed a de novo deletion on the maternally derived chromosome. Since D17S117 and D17S57 were previously reported as the outer limits for the great majority of NF1 deletions, we suggest that most NF1 patients with deletion of the entire NF1 gene are hemizygous for the same set of at least 10 additional genes, including SHGC-37343, SHGC-2390, SHGC-34232, OMG, EVI2B, EVI2A, WI-9521, WI-6742, SHGC-34334, and KIAA0160, and thus present with a relatively uniform clinical phenotype.
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PMID:A common set of at least 11 functional genes is lost in the majority of NF1 patients with gross deletions. 1084 9

Nonsense or frameshift mutations, which result in a truncated gene product, are prevalent in a variety of disease-related genes, including APC (implicated in colorectal cancer), BRCA1 and BRCA2 (breast and ovarian cancer), PKD1 (polycystic kidney disease), NF1 and NF2 (neurofibromatosis), and DMD (Duchenne muscular dystrophy). Such chain-truncating mutations can be detected using the protein truncation test (PTT). This test is based on cell-free transcription and translation of either PCR-amplified portions of the target gene or RT-PCR amplified target mRNA, followed by analysis of the product(s) for shortened polypeptide fragments. However, conventional PTT is not easily adapted to high-throughput applications because it involves SDS-PAGE followed by autoradiography or western blotting. It is also subject to human error, as it relies on visual inspection to detect the mobility of shifted bands. To overcome these limitations, we have developed a high-throughput solid-phase protein truncation test (HTS-PTT). HTS-PTT uses a combination of misaminoacylated tRNAs, which incorporate affinity tags for surface capture of the cell-free expressed protein fragments, and specially designed PCR primers, which introduce N- and C-terminal markers for measuring the relative level of shortened polypeptides produced by the chain-truncation mutation. After cell-free translation of the protein fragments, capture and detection are accomplished in a single well using a standard 96-well microtiter plate enzyme-linked immunosorbent assay (ELISA) format and chemiluminescence readout. We demonstrate the use of the technique to detect chain-truncation mutations in the APC gene using DNA or RNA from cancer cell lines as well as DNA of individuals diagnosed with familial adenomatous polyposis (FAP). HTS-PTT can also provide a high-throughput method for noninvasive colorectal cancer screening when used in conjunction with methods of enriching and amplifying low-abundance mutant DNA.
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PMID:A high-throughput nonisotopic protein truncation test. 1252 52


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