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)

One hallmark of malignant potential is dysplasia, the disruption of normal morphology. While it is generally recognized that cancer is the result of a series of genetic changes, the relationship of these alterations and their timing to the advent of dysplasia remains obscure. To address this issue, 54 small benign colorectal lesions of various malignant potential were analyzed for APC and K-RAS mutations, two alterations which have been implicated in the early stages of colorectal tumorigenesis. APC mutations were closely associated with dysplasia. In contrast, K-RAS mutations were found to be remarkably common in small nondysplastic lesions which apparently have a limited potential to progress to larger tumors. These results provide evidence that the nature and order of genetic changes can have a specific impact on both tumor morphology (e.g., dysplasia) and the likelihood of tumor progression.
 ...
PMID:Molecular determinants of dysplasia in colorectal lesions. 792 89

Pancreatic adenocarcinoma is an important cause of death from cancer throughout the developed world. There are few established environmental risk factors, but a previous history of pancreatitis and exposure to tobacco and salted food appear to be the most important. A family history of pancreatic adenocarcinoma is not common in patients with this disease, but recent research has shown that pancreatic adenocarcinoma can be a feature of cancer susceptibility syndromes associated with germline mutations in p16, BRCA1, BRCA2, and APC. This highlights the need for a full family history in apparently sporadic cases. Somatic mutations in p16, BRCA2, and APC have also been reported in pancreatic cancer; however, K-RAS mutations appear to be the commonest oncogenic alteration. Recent advances in our understanding of the basis of hereditary cancer syndromes may be applicable to the diagnosis, treatment, and possibly prevention of pancreatic adenocarcinoma in the future.
 ...
PMID:Pancreatic adenocarcinoma: epidemiology and genetics. 895 Jun 67

Tumorigenesis of colorectal cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC) has been postulated to follow a different pathway from that of sporadic colorectal tumors. A characteristic of HNPCC-associated tumors is the replication error phenotype. We studied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colorectal tumors derived from 29 families with HNPCC or a familial aggregation of colorectal cancer. By using intragenic markers, inactivation of the wild-type allele of hMLH1 was shown to occur through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability is very common and occurs early in almost all colorectal tumors from HNPCC patients. Transforming growth factor beta type II receptor (T beta RII) mutations occur in these tumors at a high frequency. Of colorectal cancers from families with HNPCC, 63% have frameshift mutations in T beta RII, compared with 10% of sporadic colorectal cancers. APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart.
 ...
PMID:Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer. 938 69

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.
 ...
PMID:Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. 1128 47

Pseudomyxoma peritonei (PMP) is a clinical syndrome characterized by mucinous ascites and peritoneal lesions composed of histologically bland to low-grade adenomatous mucinous epithelium within pools of extracellular mucin, often with an associated mucinous adenoma of the appendix. There is evidence that the peritoneal lesions in PMP are clonally derived from the associated appendiceal adenoma. Little is known about the molecular genetic alterations or hereditary factors involved in the development of appendiceal mucinous tumors and PMP. We report the only known example of appendiceal mucinous adenomas in identical twin brothers, one of whom developed PMP. We analyzed the status of the K-RAS and APC genes in these tumors using digital polymerase chain reaction and digital single nucleotide polymorphism (SNP) assay. Identical K-RAS mutations were detected in the appendiceal adenoma and peritoneal tumor from the twin with PMP, whereas the adenoma from the other twin harbored a different mutation. Digital SNP analysis demonstrated loss of heterozygosity of APC only in the adenoma from the twin without PMP but not from the appendiceal or peritoneal tumors of the twin with PMP. The adjacent normal tissue in each case retained both APC alleles. The K-RAS mutational analysis supports the view that PMP is clonally derived from the associated appendiceal mucinous adenoma. The lack of loss of heterozygosity of APC in the adenoma and peritoneal tumor from the twin with PMP suggests that loss of heterozygosity of APC is not necessarily involved in the development of all appendiceal adenomas or PMP. The different types of mutations in K-RAS and the different allelic status of the APC locus in the tumors from both twins suggest that mutation in K-RAS and loss of heterozygosity of APC occurs somatically in adenomas and is independent of the identical genetic background of the twins.
 ...
PMID:Molecular genetic analysis of appendiceal mucinous adenomas in identical twins, including one with pseudomyxoma peritonei. 1147 97

Colorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. Colorectal cancer develops as the result of the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma. The loss of genomic stability is a key molecular and pathophysiologic step in this process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. Alterations in these genes, which include APC, CTNNB1, K-RAS, MADH4/SMAD4, and TGFBR2, appear to promote colon tumorigenesis by perturbing the function of signaling pathways, such as the TGF-ss signaling pathway, or by affecting genes that regulate genomic stability, such as the mutation mismatch repair genes.
 ...
PMID:Genetic and epigenetic alterations in colon cancer. 1214 55

Tumor-associated DNA has been detected in plasma of colorectal cancer (CRC) patients using various techniques but with limited gene or mutation coverage. We report a highly sensitive scanning methodology for mutational assessment of the APC and TP53 genes, which typically pose an analytical challenge because of their significant genotypic heterogeneity as well as specific mutational scoring assays for K-RAS and BRAF. Plasma DNA isolated from 20 CRC patients were scanned for mutations in these targets without knowledge of the molecular or pathological analyses of the matched primary tumors. We chose mutation scanning technology and these molecular targets to provide a comprehensive screen for somatic mutations known to be associated with sporadic CRC. Mutations were identified with a novel denaturing high-performance liquid chromatography (DHPLC) platform that uses post-separation fluorescence technology to enable the detection of variants that represent <0.1% of the total analyzed DNA. Mutant allele specific amplification (MASA) followed by detection with the same platform was used to identify low-level target mutations (mutation scoring) in K-RAS codons 12, 13, and 61, and BRAF codon 599. Using this combined scanning and scoring approach, we were able to identify at least one mutational event in 20/20 (100%) CRC patients. The thoroughness of a mutation scanning and scoring panel may have important implications for CRC screening and disease monitoring during and following therapy.
 ...
PMID:High sensitivity scanning of colorectal tumors and matched plasma DNA for mutations in APC, TP53, K-RAS, and BRAF genes with a novel DHPLC fluorescence detection platform. 1525 69

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.
 ...
PMID:Genotype phenotype correlations in Israeli colorectal cancer patients. 1552 94

Genetic and epigenetic alterations are considered to play important roles in lung cancer. Recent studies showed that EGFR and K-RAS mutations exhibited a mutually exclusive pattern in adenocarcinoma of the lung, suggesting the presence of two independent oncogenic pathways. However, it is unknown how epigenetic alterations were involved in lung carcinogenesis mediated by EGFR or K-RAS mutation. In this study, we examined the relationship between genetic and epigenetic alterations in 164 cases of lung adenocarcinoma. Somatic mutations were determined by direct sequence of EGFR exons 18 to 21 and K-RAS codons 12 and 13. Methylation status of p16(INK4a), RASSF1A, APC, RARbeta, and CDH13, frequently methylated in lung cancer, was determined by methylation-specific PCR and the degree of methylation was defined as the methylation index. Multivariate analysis adjusted for age, sex, and smoking dose showed that the probability of having EGFR mutation was significantly lower among those with p16(INK4a) and CDH13 methylation than in those without [p16(INK4a): odds ratio (OR), 0.07; 95% confidence interval (95% CI), 0.02-0.33; CDH13: OR, 0.34; 95% CI, 0.15-0.77] and the methylation index was significantly lower in EGFR mutant cases than in wild type (OR, 0.70; 95% CI, 0.52-0.95). By contrast, K-RAS mutation was significantly higher in p16(INK4a) methylated cases than in unmethylated cases (OR, 4.93; 95% CI, 1.54-15.7) and the methylation index was higher in K-RAS mutant cases than in wild type with marginal significance (OR, 1.46; 95% CI, 0.95-2.25). Our results indicate the differences in the evolvement of epigenetic alterations between the EGFR- and K-RAS-mediated tumorigenesis and suggest the specific interaction of genetic and epigenetic changes in tumorigenesis of lung cancer.
 ...
PMID:Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers. 1645 91

Epithelial ovarian cancer (EOC) is the leading cause of death in women with gynecological malignancies. Among EOC, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) differ from the other histological types with respect to their clinical characteristics and carcinogenesis. Both tumor types are often associated with endometriosis. EAC is recently reported to be characterized by K-RAS activation and PTEN dysfunction. However, the molecular changes in CCC remain largely unknown. The aim of this review is to summarize the current knowledge on the molecular mechanisms involved in CCC tumorigenesis. The present article reviews the English language literature for biological, pathogenetic and pathophysiological studies on endometriosis-associated CCC of the ovary. Several recent studies of loss of heterozygosity (LOH), allelic loss, comparative genomic hybridization, mutation, methylation status, microarray gene-expression profiling and proteomics are discussed in the context of CCC biology. Retrograde menstruation or ovarian hemorrhage carries highly pro-oxidant factors, such as heme and iron, into the peritoneal cavity or ovarian endometrioma. A histologically normal ectopic endometrium bears genetic damages caused by iron-dependent oxidative stress. DNA damage or LOH caused by oxidative stress is a critical factor in the carcinogenic process. LOH studies have implicated the involvement of specific chromosomal regions (5q, 6q, 9p, 10q, 11q, 17q and 22q). Furthermore, the PTEN and APC (early event), p53, polo-like kinases, Emi1 and K-RAS (late event) genes may be involved in CCC carcinogenesis. The molecular pathology of CCC is heterogeneous and involves various putative precursor lesions and multiple pathways of development, possibly via genetic alteration by oxidative stress.
 ...
PMID:Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (review). 1957 61


1 2 Next >>