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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of two human familial cancer syndromes, hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis, indicates that mutations in either one of four DNA mismatch repair gene homologues or the adenomatous polyposis coli (APC) gene, respectively, are important for the development of colorectal cancer. To further investigate the role of DNA mismatch repair in intestinal tumorigenesis, we generated mice with mutations in both Apc and the DNA mismatch repair gene, Pms2. Whereas Pms2-deficient mice do not develop intestinal tumors, mice deficient in Pms2 and heterozygous for Min, an allele of Apc, develop approximately three times the number of small intestinal adenomas and four times the number of colon adenomas relative to Min and Pms2+/-;Min mice. Although Pms2 deficiency clearly increases adenoma formation in the Min background, histological analysis indicated no clear evidence for progression to carcinoma.
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PMID:Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice. 951 84

The cell undergoes a diverse range of stimulations including growth factor activation and signal transduction from adhesion receptors, such as cadherins. In the absence of a mitogenic signal from outside the cell, beta catenin is sequestered in complexes with the product of the adenomatous polyposis coli (APC) gene and a serine threonine glycogen kinase (GSK 3 beta) enabling degradation of free beta catenin. Residual catenins hold cells together by binding to cadherins both at adherens junctions and the actin cytoskeleton. When a mitotic signal is delivered by the wnt pathway, GSK 3 beta is antagonised so that beta catenin can no longer be degraded. Cytosolic concentrations rise and binding to other newly synthesised proteins occurs, especially transcription factors that are transported to the nucleus, such as lymphocyte enhancing factor and T cell factor. This article discusses the signalling between mitogenic and adhesion pathways and suggests that it is a global mechanism for development, differentiation, and disease. These changes in catenin and APC biology may not be sufficient alone to transform cells fully but they appear to be a necessary final common pathway for several cancers of the mucous secreting crypts (including Barrett's oesophageal lesions and colorectal cancer) or stratified secreting epithelium (melanoma) before invasion.
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PMID:Cadherin and catenin biology represent a global mechanism for epithelial cancer progression. 953 77

Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22.
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PMID:Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene. 954 Nov 12

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.
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PMID:Genotype-phenotype correlations in attenuated adenomatous polyposis coli. 958 11

Chain-terminating germline APC mutations are responsible for adenomatous polyposis coli (APC). In the present work, we tested the hypothesis that germline APC mutations may be present in some patients with a milder phenotype, i.e., multiple synchronous colorectal adenomas. Eighteen patients with 3 or more colorectal adenomas at endoscopy (within a 6-month period) were ascertained from a series of subjects undergoing endoscopic examination. Their blood DNAs were analysed for the presence of germline mutations in the APC coding region by single-strand polymorphism analysis. Ten unrelated polyp-free subjects and 101 unrelated APC patients were used as controls in the molecular analyses. Five of the eighteen patients carried novel germline APC variants or rare polymorphisms. These were various in site (from the splice acceptor site of intron 7 to the end of exon 15) and type (splice-site, missense, and chain-terminating mutations). Only one of ten polyp-free individuals carried a silent APC variant and none of these variants was found in the 101 APC controls. A first- or second-degree family history of colorectal cancer was reported by 4 of the 5 patients carrying a germline APC variant. In conclusion, novel APC germline variants were detected in patients with multiple synchronous adenomas. This suggests that the development of sporadic adenomas, in some instances, is associated with the presence of minor germline variants of the APC gene and that the spectrum of germline APC functional mutations may be larger than previously thought.
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PMID:Novel germline APC variants in patients with multiple adenomas. 966 63

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.
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PMID:The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. 972 71

Germ-line mutations in the APC gene cause adenomatous polyposis coli (APC), a syndrome in which patients develop hundreds to thousands of precancerous adenomatous colorectal polyps. We described previously an attenuated form of APC (AAPC) resulting from very 5' mutations in APC in which affected patients exhibit fewer colorectal polyps and a later age of onset of colorectal cancer. However, because striking variations in colorectal polyp numbers occur among patients carrying identical AAPC mutations, alleles of another gene may modify the expression of the APC disease phenotype. We tested the hypothesis that loss of function of human cyclooxygenase 2 (COX-2), known to modify the APC phenotype in the Apc delta716 mouse, results in a decreased tumor burden in AAPC patients that develop very few colorectal polyps. Genomic DNA sequence analysis of human COX-2 revealed a silent mutation in exon 3 that was evenly distributed between two classes of patients with AAPC, those with small or large numbers of colorectal polyps. We also found no difference in levels of COX-2 mRNA in transformed blood lymphocytes among AAPC patients of either class or patients with classical APC, and no alterations that correlated with a lesser or greater number of colorectal polyps were detectable within approximately the first 1 kb of the promoter sequence. Therefore, mutation of the human COX-2 gene does not appear to be responsible for a low tumor burden among AAPC subjects.
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PMID:The inducible prostaglandin biosynthetic enzyme, cyclooxygenase 2, is not mutated in patients with attenuated adenomatous polyposis coli. 980 98

To test the hypothesis whether DNA polymerases acquire mutator properties during tumor development (mutator hypothesis), we examined DNA polymerase delta mRNA in 6 colon cancer cell lines (DLD-1, HCT116, SW48, HT29, SW480 and SW620) and 7 sporadic human colorectal cancers. For analysis we used amplification of cDNA by polymerase chain reaction, single-strand conformation polymorphism and sequencing techniques. In 5 of the cell lines, 9 mutations leading to changes of the amino acid sequence of DNA polymerase delta were detected. Most mutations were found in the cell lines DLD-1, HCT116 and SW48 for which defects in mismatch repair genes had been identified previously. In the majority of cases, wild type and mutated sequences were present. In 2 cell lines (HCT116 and SW48), a single-nucleotide deletion occurred at the same position. This resulted in a premature termination codon by which the DNA interaction domain of the enzyme was eliminated. Furthermore, sequence deviations were found in the tumor tissues of 4 colon cancer patients. Wild-type and altered sequences were present simultaneously. The deviations included missense mutations (2 cases) and silent mutations (2 cases). The missense mutations and one of the silent mutations were found in normal mucosa as well. In addition, the mutation clustered region of a tumor suppressor gene, often found to be defective in colon cancer, the adenomatous polyposis coli (APC) gene, was investigated in surgical specimens and cell lines. One carcinoma and 2 cell lines exhibited amino acid changes in both the DNA polymerase delta gene and in the mutation clustered region of the APC gene. Since most of the mutations detected in the DNA polymerase delta mRNA are likely to alter the structure of the protein, the enzyme is expected to be functionally impaired. In particular, copying fidelity might be decreased, thus contributing to the high mutation rate observed in colorectal cancer.
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PMID:Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines. 1007 27

Germline mutations within the adenomatous polyposis coli (APC) gene, a tumor suppressor gene, are responsible for most cases of familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer. To date, more than 300 germ-line causative mutations within this gene have been described (Beroud and Soussi, 1996). Of these, about 95% are chain-terminating mutations, and more than 60% have been localized within exon 15 (Nagase and Nakamura, 1993, Beroud and Soussi, 1996). Using polymerase chain reaction-single strand conformation polymorphism, protein truncation test (PTT) and DNA sequencing we have identified five new frameshift mutations (2523insCTTA, 2638delA, 2803insA, 3185delAA, 4145delTCATGT), all occurring within exon 15 and giving rise to truncated protein products. Two of these new mutations are of particular interest because of the unusual phenotypic features shown by probands. The phenotype of the proband bearing the 2523insCTTA mutation at codon 842 was very aggressive with onset of the symptoms at 12 years, while the patient bearing the 3185delAA mutation at codon 1062 exhibited features of an attenuated form of FAP (AAPC). Our data reiterate the great heterogeneity of the mutational spectrum in FAP that gives rise to an extreme variability of the clinical expression.
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PMID:Familial adenomatous polyposis coli: five novel mutations in exon 15 of the adenomatous polyposis coli (APC) gene in Italian patients. Mutations in brief no. 225. Online. 1009 Apr 83

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.
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PMID:Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. 1009 63


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