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)

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.
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PMID:Drastic genetic instability of tumors and normal tissues in Turcot syndrome. 941 79

MSH6 has been implicated in repair of single base mispairs and single-base deletion/insertion mutations. Established MSH6-null mice present a frequent occurrence of gastrointestinal tumors without microsatellite instability (MI), suggesting the possibility of the APC gene being a mutational target. Because human ampullary carcinomas and gastric cancers manifest frequent missense or I-base deletion mutations in cancer-related genes such as p53 and TGFbeta-RII, we suspected that the hMSH6 gene mutation might play a role in the carcinogenesis process. Out of the whole coding sequences, hMSH6 (C)8 (codons 1085-1087) and hMSH3 (A)8 repeats (codons 381-383) have been shown to be hotspots for frameshift mutations in a certain group of cancers, contributing to an increased genomic instability. We therefore investigated mutations of hMSH6 (C)8 and hMSH3 (A)8 in association with microsatellite mutator phenotype (MMP) in 18 ampullary carcinomas and 30 gastric cancers. In addition, overexpression of the P53 protein and mutational status of APC (AG)5 (codons 1462-1465) and (A)6 (codons 1554-1556) repeats were also investigated as a potential target of genetic instability secondary to MSH6 dysfunction. Mutation of the hMSH6 gene was not found in ampullary carcinomas and was irrelevant to TGFbeta-RII gene mutation. Mutation of the hMSH6 gene was observed in a subset of gastric cancers (4/30, 13.3%), but was not associated with P53 overexpression or APC gene mutation. In contrast to MSH6-null mice that do not show MI, hMSH6 gene mutation in human gastric cancers was closely correlated with MMP (3/10 MMP vs. 1/20 non-MMP). In conclusion, hMSH6 mutation appears only in association with MMP and may underlie augmented MI, resulting in missense or I-base frameshift mutations in other genes in human gastric cancers.
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PMID:Mutations of the human MUT S homologue 6 gene in ampullary carcinoma and gastric cancer. 980 25

The majority of tumors from hereditary nonpolyposis colorectal cancer families and a subset of unselected gastrointestinal and endometrial tumors exhibit a microsatellite mutator phenotype (MMP) that leads to the accumulation of hundreds of thousands of clonal mutations in simple repeat sequences. The mutated genes with positive or negative roles in cell growth or survival in aneuploid gastrointestinal cancer (e.g., APC, K-ras, and p53) are less frequently mutated in near-diploid MMP gastrointestinal tumors. These tumors accumulate mutations in other genes, such as DNA mismatch repair hMSH3 and hMSH6, transforming growth factor-beta type II receptor, and BAX. All these genes carry, within their coding sequences, mononucleotide repeats that are preferred targets for the MMP. Endometrial carcinoma is the most common type of extracolonic neoplasia in the hereditary nonpolyposis colorectal cancer syndrome, but the spectrum of its target cancer genes is not well characterized. Here, we report that endometrial cancer of the MMP also accumulates mutations in genes that are typically mutated in gastrointestinal cancer of the mutator pathway, including BAX (55%), hMSH3 (28%), and hMSH6 (17%). We also report the detection of frameshift mutations in caspase-5, a member of the caspase family of proteases that has an (A)10 repeat within its coding region, in MMP tumors of the endometrium, colon, and stomach (28, 62, and 44%, respectively). We therefore suggest caspase-5 as a new target gene in the microsatellite mutator pathway for cancer.
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PMID:Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. 1038 66

Frameshift mutations in genes containing mononucleotide repeats are often observed in cancers exhibiting a high frequency of microsatellite instability (MSI-H). Several tumor types, including colorectal, gastric, and endometrial carcinomas, display this phenotype in a significant proportion of cases. We recently showed in a large series of MSI-H colorectal tumors that approximately 40% of them exhibited frameshift mutations in an (A)9 tract within the coding region of the TCF-4 gene, a crucial member of the APC/beta-catenin/TCF pathway. In the present study, we have examined MSI-H cancers from other primary tumor sites for mutations in this new target gene. Two of 22 (9%) MSI-H primary gastric cancers and none of 23 MSI-H endometrial primary tumors and cell lines were found to have a 1 bp deletion in the TCF-4 repeat. In the same series of tumors we also looked for frameshift mutations in other coding repeats localized within the TGF beta-RII, BAX, IGFIIR, hMSH3 and hMSH6 genes. Our results suggest that the TCF-4 gene, in a similar manner to some of these latter genes, is differentially altered in MSI-H tumors from different primary sites.
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PMID:Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability. 1059 89

So far, somatic mutations of the PTEN gene have been found in several different neoplasms but not in colorectal tumours. As exons 7 and 8 of the PTEN coding sequence contain an (A)(6)repeat and mononucleotide repeat sequences are targets for mutations in tumours with microsatellite instability (MI), we screened a panel of sporadic colorectal tumours exhibiting MI to test whether PTEN gene repeats are frequently mutated in MI(+)colorectal cancers. Of 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with consequent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D10S541, was detected in two of three informative samples. To further address the role of the PTEN gene in MI(+)colorectal cancer, in the six patients with mutated PTEN, we analysed the mononucleotide repeats of six other genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC. In two of these six patients, mutations of the TGFbRII gene only were present, indicating that PTEN may have a role in the mutator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI(+)colorectal tumours. The mutation of both PTEN alleles and evidence that the PTEN protein is expressed in normal colon suggest that loss of function of this gene could play a direct role in tumorigenesis.
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PMID:Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. 1060 39

In order to understand the role of mismatch repair (MMR) gene in colorectal carcinogenesis,microsatellite instability (MSI) status of 16 microsatellite loci of 62 adenomas from 59 patients, including sporadic and familial adeonmatous polyposis (FAP) adenomas were detected by microdissection-PCR-SSLP, and protein expressions of beta-catenin, P53, and BAX, etc. were assayed by immunohistochemistry. Results were as following: (1)The overall MSI alteration rate of the 16 loci was 14.4%. Different adenomas from the same patient showed different microsatellite alterations at the same loci; (2)All of the five FAP patients were MSI-L, three of which showed MSI at the locus of hMSH3; (3)The membrane expression rate of beta-catenin in adenomas and accompanied carcinomas was 42.9% and 11.4%, respectively (P<0.001); (4)Microsatellite alterations of the microsatellite loci of TP53, D5S346, TCF4(A)(9), TGFbetaRII(GT)(3) and TGFbetaRII(A)(10) were associated with the changes of their protein expressions. It could be concluded the following: (1)Microsatellite instability existed even in the early stage (adenomas) of colorectal tumorigenesis. The alterations of chromosome 1p, APC genes, and the TGFbeta signal transduction pathway could also be deduced; (2)In the progression of adenoma to carcinoma, the staining of beta-catenin would be transferred from membrane to cytoplasm and then nucleus, and the cytoplasm stain was stronger in carcinoma than that in adenomas. The abnormality of the signal transduction pathway of APC-beta-catenin-TCF4 could be concluded.
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PMID:[Microsatellite instability and relative gene expressions in sporadic and familial adenomatous polyposis adenomas]. 1562 58