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

Some mixed hyperplastic adenomatous polyps (MHAPs) contain dysplastic lesions or even carcinomas. These polyps are considered to be different from ordinary hyperplastic polyps and may have a preneoplastic potential. We investigated APC and K-ras mutations in MHAPs of the colon and rectum, and also in colorectal adenomas and hyperplastic polyps to identify molecular differences between MHAPs, adenomas and hyperplastic polyps, using direct sequencing of mutation cluster regions (MCR) in APC and K-ras. No APC mutations were identified in 12 MHAPs and 8 hyperplastic polyps, whereas 10 of 27 (37.0%) adenomas showed somatic mutations. K-ras mutations were identified in one of 12 (8.3%) MHAPs, one of 8 (12.5%) hyperplastic polyps, and 10 of 27 (37.0%) adenomas. p53 mutation was found in a carcinoma arising in an MHAP. Mutations other than APC mutations may play a role in the development of MHAPs.
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PMID:Genetic alterations of mixed hyperplastic adenomatous polyps in the colon and rectum. 960 Jan 24

The colon carcinogenic process is believed to begin with both genetic and morphological alterations in a few individual crypts. These select crypts, called aberrant crypt foci (ACF), are widely agreed upon as precursors of colon cancer. The ACF assay involves testing potential chemopreventive agents by counting the number of ACF in a carcinogen-treated colon. This assay has the advantage of not only being less expensive and time-consuming than tumor-producing studies, but will also allow the elucidation of the colon carcinogenic process by letting the researcher explore the changes that occur at a pre-cancerous stage. The ACF assay has been used most frequently in rodent models. In the rodent colon, ACF are easy to distinguish due to their distinct morphological, histological, and biological characteristics. In addition, the ACF assay has been used to look at specific genetic alterations in the crypts such as K-ras, p53, and APC mutations. Our laboratory has consistently used the ACF assay to test many potential chemopreventive agents using rats induced by the colon carcinogen azoxymethane (AOM). Potential chemopreventive agents have been tested in both the initiation or the post-initiation period Research supports the notion that aberrant crypt foci represent a true neoplastic lesion for colon cancer. By studying these lesions both grossly and genetically it may be possible to learn more about the causes of colon carcinogenesis. In addition, by testing new compounds through the ACF assay, it is possible not only to discover potentially new chemopreventive compounds, but also to discover the mechanisms behind them. Because of this, the ACF assay is an invaluable method that will help reveal the process of colon carcinogenesis.
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PMID:Inhibition of aberrant crypt foci by chemopreventive agents. 962 97

The presence of inactivating mutations in the transforming growth factor-beta (TGF-beta) type II receptor (RII) gene in the colon cancer suggests that it may behave like a tumour suppressor gene. RII is mutated in the majority of colon tumours exhibiting widespread microsatellite instability, a characteristic generally referred to as the replication error phenotype (RER+). We investigated the association between RII mutations and various clinicopathological variables and genetic alterations in a large series of sporadic adenocarcinomas arising in the proximal colon. RII mutations were found in 17 per cent (36/210) of right-sided tumours and in 86 per cent (32/37) of those displaying RER+. They were associated with the absence of lymph node invasion (P = 0.04), poor histological differentiation (P = 0.006), and with a trend for improved patient survival. Tumours with an RII mutation also showed non-significant trends for a lower incidence of p53 protein overexpression and of p53, K-ras, and APC gene mutation compared with tumours with normal RII. These results indicate that right-sided colorectal tumours containing RII mutations resemble those with the RER+ phenotype in terms of their clinicopathological features and genetic alterations.
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PMID:Mutation of the transforming growth factor-beta type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations. 966 4

Colorectal carcinogenesis is widely thought to follow the adenoma-adenocarcinoma sequence. However, there are two morphologically distinct subtypes of colorectal cancer (CRC), polypoid and ulcerative. We conducted a comparative study to clarify whether different combinations of some commonly involved genetic alterations (including mutations in K-ras, p53, DCC, APC, and Rb genes) may exist between polypoid- and ulcerative-type CRCs, the two morphologically distinct types of CRC. By using PCR-based RFLP, single-strand conformational polymorphism, and loss of heterozygosity analysis, we found that K-ras codon 12 mutation was preferentially involved in polypoid tumor (P < 0.0001). There were no other significant correlations with p53 point mutation or loss of heterozygosity in chromosomes 5q, 17p, and 18q and Rb gene, which have been suggested to be involved in the progression of CRC of both morphological types. Therefore, different combinations of molecular genetic alterations may be involved in morphologically distinct types of colorectal carcinogenesis, and the K-ras codon 12 mutations may play an important role in polypoid growth of CRC. These results shed light on the function of K-ras oncogenes involved in colorectal carcinogenesis and may be important in the future design of genetic screening programs, determination of prognosis, and treatment for patients with CRC.
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PMID:K-ras codon 12 mutation determines the polypoid growth of colorectral cancer. 969 57

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.
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PMID:Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. 985 45

Objective. We studied the molecular abnormalities involved in the pathogenesis of endocrine tumors of the uterine cervix. Methods. We obtained DNA from precisely microdissected archival tissue from 15 endocrine tumors of the uterine cervix, consisting of 5 carcinoids (1 typical, 4 atypical), 2 large cell neuroendocrine carcinomas, and 8 small cell carcinomas. We investigated the presence of high-risk (types 16 and 18) and intermediate-risk (types 31 and 33) human papilloma virus (HPV) sequences, TP53 and K-ras gene mutations, and loss of heterozygosity (LOH) at 9 genes/chromosomal regions, including 3p14.2/FHIT, 3p14-p21, 3p21, 3p22-p24, 5q21-q22/APC-MCC region, 9p21/CDKN2, 11q23/MEN1, 13q/RB, and 17p/TP53. Results. HPV sequences were detected in 8 (53%) tumors, HPV 16 in 2 cases, and HPV 18 in 2 cases. LOH at 9p21 (43%) and localized 3p deletions (47%) were the most frequent allelic losses found. Allelic losses at 5q21-q22/APC-MCC region, 11q23/MEN1, and 13q/RB were infrequent. TP53 gene mutations were detected in 7 (47%) tumors (1 atypical carcinoid and 6 carcinomas). HPV sequences were demonstrated in 4 of the 7 cases with TP53 gene mutations. No K-ras mutations were detected. Conclusion. The molecular changes present in endocrine tumors of the uterine cervix have distinct features. They incorporate those present in the neuroendocrine tumors of the lung (high frequency of TP53 gene abnormalities and 9p21 deletions) with those detected in squamous cell carcinomas of the cervix (high-risk HPV sequences and localized 3p deletions).
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PMID:Molecular abnormalities associated with endocrine tumors of the uterine cervix. 988 21

Although most gallbladder carcinomas evolve from dysplasia and carcinoma in situ, the role of gallbladder adenomas in the pathogenesis of gallbladder carcinoma is still controversial. A series of molecular changes including loss of heterozygosity (LOH) at 17p (TP53 gene), 13q (RB gene), 18q (DCC gene), and 9p21 (CDKN2a gene) chromosomal regions have been identified in dysplasias, carcinomas in situ, and invasive carcinomas of the gallbladder, whereas mutations in K- and N-ras genes are rare. To determine whether the molecular abnormalities of adenomas are similar to those found in carcinomas, we obtained extracted DNA from precisely microdissected tissue from 16 gallbladder adenomas (14 pyloric and 2 intestinal-type). We determined the presence of mutations in TP53, K- and N-ras genes, and LOH at five chromosomal regions (5q22 APC-MCC region, RB, TP53, DCC and 9p21-CDKN2a). For the TP53 mutation study, single strand conformational polymorphism (SSCP) analysis in exons 4 to 8 were performed. K- and N-ras mutations detection was performed by designed restriction fragment length polymorphism (RFLP) method and sequencing. Only a single LOH (at 5q22) was detected in a gallbladder adenoma of intestinal type. No mutations at the TP53 were detected. Four adenomas (25%) showed K-ras mutations (two in codon 12 and two in codon 61). We conclude that gallbladder adenoma lacks the molecular changes frequently detected in dysplasia, carcinoma in situ, and invasive carcinoma of the gallbladder. Likewise the occurrence of K-ras mutations at codon 12 and 61 in 25% of adenomas strongly suggests that these lesions are not precursors of invasive gallbladder carcinoma.
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PMID:Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas. 992 22

We performed molecular biological studies as well as immunohistochemical analysis of three cases of giant cell carcinoma of the pancreas. Histologically, one case was a pleomorphic giant cell carcinoma consisting of pleomorphic giant/ small cells and spindle cells, one an osteoclast-like giant cell tumor composed of osteoclastoid giant cells and pleomorphic small cells, and one a pleomorphic giant cell carcinoma with osteoclastoid giant cells. Immunohistochemically, pleomorphic giant cells and small pleomorphic cells were positive for epithelial and mesenchymal markers throughout the cases. Osteoclastoid cells were strongly positive for PG-M1 (CD68), but negative for lysozyme and epithelial markers. Pleomorphic spindle cells showed the same immunoreactivity as pleomorphic giant/small cells. Genetically, all cases contained a mutation in the K-ras (codons 12, 13) oncogene, but neither p53 (exons 5-8) nor p16INK4 (exons 1, 2) gene mutations were found in any case. Furthermore, Loss of heterozygosity (LOH) of the p53, p161NK4. APC, and DPC4 gene loci was not found in any of the cases. Immunohistochemical study demonstrated this tumor to be of epithelial origin with mesenchymal differentiation. Genetically, initiation of the tumor is similar to that of usual ductal adenocarcinoma, but progression might be rather different. The peculiar histologic and biologic features of this tumor would be the result of changes in other functional genes.
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PMID:Immunohistochemical and molecular analysis of giant cell carcinoma of the pancreas: a report of three cases. 1020 90

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor in liver; however, the carcinogenic mechanism of ICC is poorly understood. To analyze the molecular carcinogenesis of ICC, we examined the alterations of the p53, APC, and K-ras genes in 40 surgically resected ICC cases. The single-strand conformation polymorphism/sequencing revealed a p53 mutation in 12 cases (30%). An immunohistochemical overexpression of the p53 gene was detected in 10 cases (25%). The PCR/RFLP showed loss of heterozygosity of APC in 4 of 17 informative cases (23.5%). And the PCR/RFLP assay of K-ras codon 12 revealed the mutation in nine cases (22.5%). Twenty-one cases (52.5%) showed an alteration of at least one of the examined genes, and six (15%) carried an abnormality in more than two genes. The analysis of the clinicopathologic findings disclosed a significant relationship between the genetic alteration and gross type of the tumor: the p53 mutation was prominent in the ICC of mass-forming type, and K-ras mutation occurred more frequently in the ICC of periductal extension type (p < 0.05). These data suggest that each of the examined genes is involved in the development of ICC and that the p53 and K-ras mutation may play a role in the tumor growth pattern.
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PMID:Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma. 1021

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


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