Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a signaling protein in the Wnt pathway beta-catenin plays a crucial role in the regulation of cellular proliferation. Recently, oncogenic beta-catenin mutations were described in human colorectal cancer and melanoma cell lines. Since activating mutations in the beta-catenin gene have similar effects on the biochemical level as inactivating mutations in the tumor suppressor gene APC, it is speculated that beta-catenin mutations may substitute APC gene inactivation in carcinogenesis. To address this question we analyzed twenty-three sporadic colorectal tumors of different progression states for mutations in the beta-catenin gene. Eighteen of these tumors showed the wildtype APC gene sequence. In only one of the tumors with wildtype APC a beta-catenin gene mutation was found. This tumor was of the RER (replication error) phenotype which may explain the finding that the mutation occurred in a sequential repeat motif of the beta-catenin gene. The second aim of this study was to investigate whether differences in the phenotypic variability in FAP (familial adenomatous polyposis coli) might be due to inherited alterations in the beta-catenin gene. For this we analyzed DNA from fourteen FAP patients from eight different families for germline mutations in the beta-catenin gene. We did not find any beta-catenin gene alteration in these samples. Our results indicate that somatic beta-catenin activating mutations contribute only to a minor part of human colorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP.
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PMID:A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients. 959 32

Patterns of allele loss (loss of heterozygosity, LOH) have been studied in order to investigate the genetic pathways involved in the pathogenesis of three types of colorectal cancer (CRC): sporadic CRC without replication errors (RER-) (32 cases); sporadic RER+ CRC (23 cases); and ulcerative colitis-associated CRC (UCACRC) (16 cases). Each tumour was assessed for allele loss at ten microsatellite markers which map close to known or putative tumour-suppressor genes: APC (5q21-q22); DCC (18q21.1); 1p35-p36; p16 (9p21); 22q; 8p; E-cadherin (16q22.1); beta-catenin (3p22-p21.3); RB1 (13q14.1-q14.2); and HLA. Overall, high frequencies of allele loss (> 30 per cent) were found near DCC (42 per cent), p16 (38 per cent), 22q (37 per cent), 1p35-p36 (34 per cent) and APC (31 per cent), and low frequencies (< 20 per cent) near RB1 (16 per cent) and E-cadherin (13 per cent). LOH near beta-catenin, HLA, and on 8p occurred at frequencies between 20 and 30 per cent. The overall frequency of allele loss did not differ among the three tumour groups, but some variation was seen at individual loci. There was a significantly higher frequency of LOH at 1p35-36 in RER+ tumours compared to RER- tumours. Allele loss at this site was also associated with a more advanced Dukes' stage at presentation. In addition, RER- tumours showed a higher frequency of allele loss at p16 than RER+ tumours. No significant difference existed at any locus between the frequency of LOH in sporadic CRC and in UCACRC. Pairwise analysis showed a negative association between LOH at APC and DCC, and between LOH at chromosome 22p and p53 overexpression. Thus, there may be specific differences between the mutation spectra of RER+ and RER- CRCs, but there are large degrees of overlap among the underlying genetic pathways of these cancers and UCACRCs.
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PMID:A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. 960 5

Somatically acquired mutations in several genes have been reported as playing an important role during colorectal tumorigenesis. Two alternative groups of carcinomas, termed LOH+ and RER+, have been defined on the basis of their genetic anomalies, a biallelic inactivation of the APC or the TGF-betaRII genes, occurring as an alternative, in LOH+ or RER+ tumors. It is a generally accepted hypothesis that most of colorectal cancers (CRC) develop from a pre-existing adenomatous polyp. Such benign lesions are usually exophytic polyps, a small proportion of adenomas having been described as flat lesions. The latter histological category has thus been proposed to bear specific genetic alterations. In order to examine this hypothesis, we have characterized a series of 44 flat colorectal neoplasias for their RER status and for somatic APC, KRAS and TGF-betaRII genes mutations. Flat colorectal neoplasias were found to be of the RER+ subtype in 22% of cases, all of them exhibiting a TGF-betaRII mutation. A mutation of the APC and KRAS genes has been found in 42% and 4% of tumors, respectively, none of these tumors being of the RER+ subtype. With the exception of a low KRAS mutation rate, flat adenomas appear to follow tumorigenesis pathways very similar to those identified in exophytic adenomas and carcinomas.
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PMID:Somatically acquired genetic alterations in flat colorectal neoplasias. 966 97

Our aim was to reveal the significance of tumor-suppressor genes and genomic instability in 99 Hong Kong Chinese colorectal carcinoma (CRC) patients by PCR-LOH analysis and PCR-PTT assay. The frequencies of allelic loss of Apc, Mcc and Dcc and of APC truncation were 31.3% (15/48), 11.6% (5/43), 44.4% (20/45) and 46/93 (49.5%), respectively. The frequency of Apc LOH was similar to, the Mcc LOH was lower than, and the Dcc LOH was higher than that reported for Caucasians and Japanese. In Hong Kong CRC patients, the replication error-positive (RER(+)) phenotype occurred with a frequency of 10% (10/99), which was similar to other results using microsatellite markers where RER(+) frequencies ranged from 11% to 28%. The rates of genetic alteration in RER(+) tumors were lower in tumors harboring p53, Mcc and Dcc alterations; similar in Apc; and higher in Ki-ras tumors compared with RER(-) tumors, though these differences did not achieve statistical significance. None of the biomarkers examined were predictive of survival independently, but strong trends confirming earlier observations of associations between RER(+) phenotypes with proximal tumor location and poorly differentiated tumor status were noted. The RER(+) phenotype was correlated significantly to the less aggressive Duke's stage B and improved prognosis. Additionally, tumors with RER(+) phenotypes were positively correlated with young age and sex. Our results support the observation that a subset of younger male CRC patients in Hong Kong may develop CRC via the RER pathway and show differences in RER status and sex. A significantly higher percentage of older Hong Kong Chinese CRC patients had APC truncations. Int. J. Cancer (Pred. Oncol.) 84:404-409, 1999.
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PMID:Genomic instability and alterations in Apc, Mcc and Dcc in Hong Kong patients with colorectal carcinoma. 1040 94

Over past three decades in Poland we have seen a steady increase in the incidence of colorectal cancer. It is unclear whether this phenomenon is associated with changes in biology of the disease. In the present study we compared basic clinical data and pathological features of colorectal carcinomas submitted as resection specimens to a single institution in 1975 (n=76) and 1995 (n=106). We found a significant increase in sigmoid tumors (15.8% in 1975, 34.9% in 1995, P=0.0028), a decline in the frequency of mucinous carcinomas (22.4% in 1975, 7.5% in 1995, P=0.0041), and reversed distribution of low- and high-grade tumors (more high-grade than low-grade carcinomas in 1975, the opposite in 1995). We observed trends toward more pronounced peritumoral desmoplastic response, less prominent chronic peritumoral inflammatory infiltrate, and more frequent perineural invasion. The 1995 patients were on average significantly older at surgery (59 years in 1975, 64 years in 1995, P=0.02) and had smaller tumors (max. diameter=5.49 cm in 1975, 4.27 cm in 1995, P=0.0018). There were no differences in distribution of tumor stage, patient's sex, type of infiltrating margin formed by carcinomas, relative amount formed by the solid tumor component, invasion of veins and lymphatics, or presence of an adenoma contiguous with a carcinoma. Differences between 1975 and 1995 cases observed in our material probably reflect the changing biology of colorectal carcinoma in Poland. Mucinous, high-grade, proximal tumors, surrounded by prominent chronic inflammatory infiltrate, diagnosed in relatively younger subjects are associated with familial and sporadic cancers due to widespread genomic instability (replication error positive or RER(+) phenotype). We conclude that in Poland the APC/K-ras/p-53 carcinogenesis pathway is becoming even more important than the carcinogenesis characterized by RER(+) tumors. This study is a starting point for further investigations aimed at confirming this hypothesis.
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PMID:Preliminary report on pathology of colorectal cancer in Poland in 1995 and 1975: is it still the same disease? 1066 94

Somatic APC mutations in colorectal tumors with an RER phenotype reflect excessive frameshift mutations, especially in simple repetition tracts within the coding sequence. Because this type of mutation is characteristic of cells with a deficient DNA MMR system, the APC mutation signature of RER tumors may be attributable to a defect in the MMR system. However, there is little experimental evidence to prove that the spectrum of mutations and the APC gene distribution are directly influenced by MMR system defects. We therefore examined the mutation spectrum of the MCR of the APC gene after transfection into both MMR-proficient and MMR-deficient yeast strains and compared it with a previously reported human APC mutation database. Small insertions or deletions in mono- or dinucleotide repeats were more common in the MMR-deficient than in the MMR-proficient strain (91.2% vs. 38.1%, Fisher's exact test p < 0.0001). Furthermore, the 2 mutation hot spots, 4385-4394(AG)(5) and 4661-4666(A)(6), found in the yeast system corresponded with those in human tumors. Combining our data with those from human tumors, there appears to be hypermutable mutations in specific simple repetitive sequences within the MCR, which are more prevalent in MMR-deficient cells and RER tumors than in MMR-proficient cells and non-RER tumors. We therefore consider that the differences in the spectra of RER and non-RER tumors are attributable at least in part to the MMR system of the host cells.
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PMID:Analysis of the human APC mutation spectrum in a saccharomyces cerevisiae strain with a mismatch repair defect. 1249 69

Familial adenomatous polyposis (FAP) is an autosomal dominant illness with the highest risk for appearance of colorectal cancer's disease. In our study, we have used Bethesda criteria that define colorectal cancers which can be tested on microsatellite instability. The aim of our study is make an analysis of microsatellite instability (MSI), appearance of RER+ phenotype, genetic alteration of tumor suppressor genes as like as one of responsible factor for genesis of adenomatous polyposis. The base for this study were shown families with clinical diagnosed FAP. In this study two families with clinical diagnosed adenomatous polyposis were involved. Our study of both families showed that three tumor tissues belonged to RER negative phenotype, but only one belonged to RER positive phenotype. Microsatellite analysis showed instability of mononucleotide marker Bat 40 at 4 samples and Bat 26 at 2 samples, but Bat 25 and in 1 sample. Dinucleotide marker TP 53 did no show any microsatellite alterations. Genetic alteration of tumor suppressor gene APC appeared at 4 samples, p53 at 3 samples, RB1 at 2 samples and NM23 only at 1 sample, but tumor suppressor genes DCC1 and DCC2 were homozygote. Our results are agree with results of earlier studies and also the got results confirm the fact that loss of heterozygosity of tumor suppressor gene APC and p53 are responsible for genesis of adenomatous polypose and it also represents the characteristic of genetic changes FAP's patients in our region.
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PMID:Familial adenomatous polyposis: analysis of genetic instability of microsatellites Loci and genetic alternations of tumor suppressor genes. 1849 68

Considering its frequency, high mortality rate as well as many etiological mysteries colorectal cancer is a challenge to contemporary science. In our study we analyzed RER + and RER--phenotypes and their relations with clinical-pathological characteristics of sporadic colorectal cancers. We also analyzed genetic alterations of tumor suppressor genes as well as their relation with microsatellite instability. The study was based on 54 tumor samples and 54 samples of the surrounding healthy tissue of patients with colorectal cancer. According to Amsterdam Criteria and Bethesda Criteria 35/54 or 64,81% belonged in the group of sporadic colorectal cancer. Mononucleotide marker Bat 25 showed instability in 48,57%; Bat 26 in 45,71% and Bat 40 in 29/35 82,86% of tumor samples. Considering dinucleotide markers, TP 53 showed instability in 54,29% and DS123 in 37,14% of tumor samples. Genetic alterations in tumor suppressor genes were found in tumor tissue: NM 23 in 54,29% samples, p53 in 51,43%, APC in 51,43%, DCC2 in 34,29%, RB1 in 22, 86% and DCC 1 in 28,57%. Our studies confirmed that genetic instability had an important role in the development of tumor type. Our results showed that mononucleotide marker Bat 40 might be used for an easy and fast screening procedure in Bosnian population, because it exhibited high percent of microsatellite instability and was in relation with RER+ phenotype. This investigation showed that different genetic alterations may occur during cancer development in each individual patient's tumor. These changes result in MMR inactivation, which causes RER+ phenotype. Our results suggest a connection between alteration in some tumor suppressor genes and MSI phenotype of sporadic colorectal cancer in Bosnian population.
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PMID:Microsatellite instability and loss of heterozygosity of tumor suppressor genes in Bosnian patients with sporadic colorectal cancer. 1912 1