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)

In most cases the analysis of DNA mutations in presence of a high excess of wild type DNA fail because of the low sensitivity of the performed method for mutation detection. Here we describe the new high-sensitive and non-radioactive HD-PCR method (for HeteroDuplex-PCR). In opposite to the conventional analytical application the heteroduplex technique is performed to preparatively separate mutated from non-mutated PCR amplified DNA fragments. We used the new method to detect mutations in the tumor suppressor gene APC in stool DNA from patients with sporadic colorectal carcinomas. Since the alteration of the APC gene occurs early in most colorectal tumors, the detection of APC mutations in fecal tumor DNA by HD-PCR may be a powerful tool in non-invasive cancer diagnostics.
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PMID:Detection of APC mutations in stool DNA of patients with colorectal cancer by HD-PCR. 945 Sep 8

Precise correlation of histomorphology with the results of molecular genetic analysis is difficult in gastric cancer tissue composed of intestinal and diffuse types. A novel microdissection procedure was applied to correlate p53 and APC allelic loss with histologic type and tumor stage (mucosal vs. invasive cancer) in formalin-fixed, paraffin-embedded specimens of 25 gastric cancers. In addition, mucosal and invasive lesions were dissected from each of 11 invasive gastric cancers to study progression, and allelic loss of the p53 and APC genes was assessed. The p53 gene underwent loss of heterozygosity (LOH) in 4 of 4 informative cases of intestinal-type gastric cancer with mucosal lesions associated with invasion. By contrast, no p53 LOH was found among 6 informative cases with mucosal cancer. LOH of the APC gene in both intestinal and diffuse types of cancer was detected in 4 of 7 and 5 of 6 informative cases, respectively. These data suggest that allelic deletion of the p53 gene in intestinal-type gastric carcinoma predicts the invasive potential of mucosal cancer, and that inactivation of the APC gene plays a role in the genetic tumorigenesis of both intestinal and diffuse types of gastric cancer. Microdissection can correlate genetic alterations with histologic morphology in gastric cancer.
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PMID:Correlation of histologic morphology and tumor stage with molecular genetic analysis using microdissection in gastric carcinomas. 999 Apr 80

The incidence of adenocarcinoma of the distal esophagus is rapidly increasing in the Western world. The histopathological sequence of (Barrett's) metaplasia, which develops as a consequence of chronic reflux, to dysplasia and then to carcinoma is well established for these tumors. In Barrett's esophagus a variety of molecular changes have been characterized and correlated with tumor initiation and progression. Among the early changes in premalignant stages of metaplasia are alterations of the transcripts of FHIT, a presumptive tumor suppressor gene which spans the common fragile site FRA3B. Mutations of p53 seem to accumulate mainly in the transition from low to high grade dysplasia. Inactivation of other tumor suppressor genes by mutation (APC, p16) or hypermethylation (p16) as well as amplification of oncogenes such as cerbB2 are relatively late events in the development of adenocarcinoma. Among the phenotypic changes in Barrett's esophagus are an expansion of the Ki67 proliferation compartment which correlates with the degree of dysplasia. Moreover, accumulation of rab11 molecules which are involved in membrane trafficking has been reported to be specific for the loss of polarity seen in low grade dysplasia. Reduced expression of the cadherin/catenin complex as well as increased expression of various proteases develop chiefly in invasive carcinomas. Despite the progress that has been made in the identification of molecular markers in Barrett's carcinoma, to date the histopathological diagnosis of high grade dysplasia in endoscopic biopsies remains the best predictor of invasive cancer. Immunohistochemistry applying a panel of antibodies including p53, Mib-1 or rab11 can be helpful to diagnose regenerative metaplastic epithelium or low and high grade dysplasia.
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PMID:The molecular pathology of Barrett's esophagus. 1021 17

Esophageal adenocarcinoma (EAC) is thought to develop through a multistage process in which Barrett's metaplasia progresses through low- and high-grade dysplasia to invasive cancer. Transcriptional silencing of tumor suppressor genes by promoter CpG island hypermethylation has been observed in many types of human cancer. Analysis of CpG island hypermethylation in EAC has thus far been limited to the CDKN2A (p16) gene. In this study, we extend the methylation analysis of EAC to include three other genes, APC, CDH1 (E-cadherin), and ESR1 (ER, estrogen receptor alpha), in addition to CDKN2A. Molecular analysis can provide insight into the complex relationships between tissues with different histologies in Barrett's esophagus and associated adenocarcinoma. Therefore, we have mapped the spatial distribution of methylation patterns in six esophagectomy cases in detail. Hypermethylation of the four CpG islands was analyzed by the MethyLight technique in 107 biopsies derived from these six patients for a total of 428 methylation analyses. Our results show that normal esophageal squamous epithelium is unmethylated at all four CpG islands. CDH1 is unmethylated in most other tissue types as well. Hypermethylation of ESR1 is seen at high frequency in inflammatory reflux esophagitis and at all subsequent stages, whereas APC and CDKN2A hypermethylation is found in Barrett's metaplasia, dysplasia, and EAC. When it occurs, hypermethylation of APC, CDKN2A, and ESR1 is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.
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PMID:Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma. 1101 22

To understand the role of gene promoter methylation in neoplastic evolution and progression, the methylation changes associated with 15 candidate tumor suppressor genes were studied throughout stages of tumor progression involving intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Genomic DNA from 28 pancreatic IPMN tissue samples, categorized histologically as non-invasive intraductal IPMN (n = 3), IPMN with carcinoma in situ (n = 7), IPMN with microinvasion <1 mm (n = 4), and infiltrative IPMN with associated adenocarcinoma (n = 14), was modified by bisulfite treatment and analyzed with methylation-specific PCR (MSP). Promoter methylation of at least one tumor suppressor gene was present in 26/28 (92%) of the IPMNs. The cell cycle control genes, p16 and p73, were methylated frequently (>50%) in both non-invasive and invasive tumors. APC methylation was discovered in <10% of the non-invasive IPMNs versus 45% of the IPMNs associated with infiltrative adenocarcinoma, P = 0.040. Mismatch repair genes, hMLH1 and MGMT, were frequently methylated in the invasive IPMNs compared with the non-invasive tumors (38 versus 10% and 45 versus 20%, respectively) as was E-cadherin (38 versus 10%), P = 0.11. Multiple gene methylation at greater than three loci was present in 55% of the invasive tumors compared with 20% of the non-invasive tumors, P = 0.075. Lymph node status did not predict multi-gene methylation among tumors associated with invasive cancer. Compared with non-invasive IPMNs of the pancreas, IPMNs associated with adenocarcinoma demonstrate higher rates of aberrant tumor suppressor gene methylation. The sequential acquisition of hypermethylation at multiple gene promoter sites may explain tumor progression in IPMNs and other malignancies. Detection of methylation within selected genes may afford an accurate diagnostic molecular marker and predictor of neoplastic behavior.
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PMID:Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. 1258 67

Cancer results if regulatory mechanisms of cell birth and death are disrupted. Colorectal tumorigenesis is initiated by somatic or inherited mutations in the APC tumor suppressor gene pathway. Several additional genetic hits in other tumor suppressor genes and oncogenes drive the progression from polyps to malignant, invasive cancer. The majority of colorectal cancers present chromosomal instability, CIN, which is caused by mutations in genes that are required to maintain chromosomal stability. A major question in cancer genetics is whether CIN is an early event and thus a driving force of tumor progression. We present a new mathematical model of colon cancer initiation assuming a linear flow from stem cells to differentiated cells to apoptosis. We study the consequences of mutations in different cell types and calculate the conditions for CIN to precede APC inactivation. We find that early emergence of CIN is very likely in colorectal tumorigenesis.
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PMID:Linear model of colon cancer initiation. 1472 9

Colorectal cancer (CRC) is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors. CRC develops through a gradual accumulation of genetic and epigenetic changes, leading to the transformation of normal colonic mucosa into invasive cancer. CRC is one of the most prevalent and incident cancers worldwide, as well as one of the most deadly. Approximately 1235108 people are diagnosed annually with CRC, and 609051 die from CRC annually. The World Health Organization estimates an increase of 77% in the number of newly diagnosed cases of CRC and an increase of 80% in deaths from CRC by 2030. The incidence of CRC can benefit from different strategies depending on its stage: health promotion through health education campaigns (when the disease is not yet present), the implementation of screening programs (for detection of the disease in its early stages), and the development of nearly personalized treatments according to both patient characteristics (age, sex) and the cancer itself (gene expression). Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application, not all strategies meet the criteria required for screening tests in population programs; the three most accepted tests are the fecal occult blood test (FOBT), colonoscopy and sigmoidoscopy. FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe. Due to its non-invasive nature and low cost, it is one of the most accepted techniques by population. CRC is a very heterogeneous disease, and with a few exceptions (APC, p53, KRAS), most of the genes involved in CRC are observed in a small percentage of cases. The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy. In recent years, the use of DNA, RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis. Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA, RNA or proteins in the blood or stool, it is likely that given the quick progression of technology tools in molecular biology, increasingly sensitive and less expensive, these tools will gradually be employed in clinical practice and will likely be developed in mass.
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PMID:Colorectal cancer: from prevention to personalized medicine. 2494 69