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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular genetics is a tool that can be learned as a language to assist clinicians in the management of colorectal cancer patients. Following a brief review of the genetic controls of colorectal cancer, the author focuses on the models of the Registry for Familial Adenomatous Polyposis and the Registry for Hereditary Nonpolyposis Colon Cancer to demonstrate most vividly the impact molecular genetics is currently having on the practical management of colon cancer. Recent discoveries of K-ras oncogene mutations in stool cultures and the prognostic implications of mutations of the TP53 and DCC genes are discussed in the context of future applications to the management of patients.
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PMID:Contributions of molecular genetics to the clinical management of colorectal cancer. 855 21

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).
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PMID:Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. 857 18

The DCC (deleted in colorectal cancer) gene was originally identified as a candidate tumour suppressor gene in colon carcinogenesis on the basis of allelic losses in chromosome 18q.21 in 70% of colon cancers. Reverse transcriptase polymerase chain reaction (RT-PCR) of DCC mRNA suggests that DCC expression may also be reduced in colon cancers. We have used monoclonal antibodies generated against the DCC immunoglobulin-like domain to investigate DCC isoforms and DCC protein expression during colon cancer progression. Normal mucosa and colonic tumour specimens representative of the range of colonic tumour progression from benign adenomatous polyps to metastases were compared by Western blot analyses. We show that while M(r) 194 000 DCC is present in normal colonic mucosa and adenomatous polyps, it is also similarly expressed in colorectal carcinomas and colonic metastases in the liver. The presence of DCC protein is consistent with the presence of DCC mRNA transcripts in the same tissue specimens. Notably DCC was not completely lost in any colonic tumour specimens examined, even those that had progressed to metastatic cancers. Quantitation of DCC protein expression in tissue specimens by densitometry demonstrated that both normal and malignant specimens exhibit a wide range of DCC protein levels and there was no significant correlation between diminished DCC protein expression and colon cancer progression. These results demonstrate the pattern of expression of the DCC gene product in colonic tumour progression and show that absence of DCC expression is not associated with colonic tumour progression.
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PMID:The deleted in colon cancer (DCC) gene is consistently expressed in colorectal cancers and metastases. 876

Karyotyping and polymorphisms within the DCC (deleted in colon cancer) locus (18q21) were used to analyze loss of chromosome 18 in squamous cell carcinomas (SCC). Tumors from 26 patients (including 7 for whom matched tumor and normal DNA samples were available) were examined for heterozygosity within DCC. Of the seven normal-tumor combinations, four were informative. Two of these had loss of heterozygosity (LOH) at DCC. For 19 SCC tumor cultures normal tissue was not available. These were scored only as homozygous or heterozygous. The majority were homozygous. Only 3/19 (15%) were heterozygous. In contrast, in a panel of normal blood samples the majority, 11/16 (69%), were heterozygous. Allelic zygosity was concordant with the chromosome 18 content in the 16 tumors that were also karyotyped. Tumors from 40 patients, 37 that were karyotyped and three that were informative at the DCC locus, were assessed for loss of chromosome 18 and patient survival. Loss of part or all of chromosome 18 occurred in tumors from 25. Twenty-seven of the 40 patients have died and 13 are alive. There was strong association between loss of 18 and overall survival. Of those who are alive only 5/13 (38%) had loss of 18, whereas among those who have died 20/27 (74%) had loss of 18. By chi 2 analysis the association of loss of 18 and death from cancer was significant (p > 0.01). The high frequency of chromosome 18 loss in SCC suggests that this region contains one or more tumor suppressor genes important in the clinical behavior of SCC. DCC is one candidate, but other regions of loss not including the DCC locus indicate that chromosome 18 probably contains more than one tumor suppressor locus. Prospective studies of chromosome 18 loss as a single prognostic indicator are strongly indicated in this tumor type since loss in early stage tumors might indicate a need for more aggressive therapy than would be given on the basis of staging alone.
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PMID:Loss of 18q and homozygosity for the DCC locus: possible markers for clinically aggressive squamous cell carcinoma. 881 36

Inactivation of the DCC (Deleted in Colon Carcinoma) tumor suppressor gene by allelic loss and/or reduced expression is associated with the development of colon cancer, gliomas, gastric and prostatic malignancies. In a total cohort of 51 testicular germ cell tumors (GCT) of different histologies we analyzed restriction fragment length polymorphism (RFLP) for DCC at two specific DNA sites in 37 GCT and DCC mRNA expression compared to that of the adjacent normal testicular tissue in 41 GCT, one Leydig cell tumor and one testicular metastasis of a non-small cell lung cancer (NSCLC). Two of 17 tumors (11.7%) informative for the Msp I polymorphic site of the DCC gene and 6/25 tumors (24.0%) informative for variable number of tandem repeat (VNTR) showed loss of heterozygosity (LOH). DCC expression was analyzed by semi-quantitative polymerase chain reaction after initial reverse transcription (RT-PCR). Thirty of 41 GCT (73.1%) and both, the Leydig cell tumor and the testicular metastasis of NSCLC, had a nearly complete or total loss of DCC mRNA expression. Six of 11 (54.5%) seminomas and 24/30 (80.0%) nonseminomas had this loss of expression. Twelve of 17 (70.5%) localized tumors, 9/13 (69.2%) tumors with lymph node involvement and 9/11 (82.2%) tumors with distant metastases showed decreased or absent DCC expression. This data suggests that inactivation of the DCC gene, especially the loss of DCC expression, is associated with the development and progression of human GCT.
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PMID:Analysis of the DCC tumor suppressor gene in testicular germ cell tumors: mutations and loss of expression. 911 74

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
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PMID:Molecular biology of colorectal cancer. 943 4

Barrett's esophagus carries a 30- to 100-fold increased risk of adenocarcinoma, which is thought to develop via a metaplasia-dysplasia-carcinoma progression. A common genetic abnormality detected in Barrett's adenocarcinoma is loss of heterozygosity (LOH) at the sites of known or putative tumor suppressor genes, of which there are at least 9 associated with esophageal adenocarcinoma. The aim of this study was to identify at which histological stage of carcinogenesis LOH at these sites occur. Microdissection of multiple paraffin-embedded tissue blocks from 17 esophagogastrectomy specimens of adenocarcinoma arising in Barrett's esophagus yielded areas of metaplasia, low-, intermediate- and high-grade dysplasia, and carcinoma. LOH analysis of microdissected tissues was performed using a double polymerase chain reaction technique with 11 microsatellite primers shown previously to have LOH in at least 30% of esophageal adenocarcinomas. Identical LOH was detected in premalignant and malignant tissues in 4 of 17 patients, and was located at 5q21-q22 (D5S346 primer), 17p11.1-p12 (TCF2 primer), 17p13.1 (TP53 primer), 18q21.1 (detected in colon cancer tumor suppressor gene [DCC] primer), and 18q23-qter (D18S70 primer). These results suggest that LOH at the sites of the DCC, adenomatous polyposis coli (APC), and TP53 tumor suppressor genes occur before the development of adenocarcinoma in Barrett's esophagus, and so merit further study as potential biomarkers of neoplastic progression in patients with Barrett's esophagus undergoing endoscopic and histological surveillance.
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PMID:LOH at the sites of the DCC, APC, and TP53 tumor suppressor genes occurs in Barrett's metaplasia and dysplasia adjacent to adenocarcinoma of the esophagus. 1066 31

The colorectal adenoma-carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-ras, K-ras, p53, DCC and the DNA repair genes hMLH1/hMSH2. In accordance with the suggested adenoma-carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ.
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PMID:Genetic analysis of multiple synchronous lesions of the colon adenoma-carcinoma sequence. 1075 1

Our previous results indicated that the trihydroxamate ligand, trisuccin, was a promising bifunctional chelating agent (BCA) for radiometal labeling of monoclonal antibodies with rhenium and technetium. An interest was developed to evaluate structural modifications of this compound from both synthetic and biological points of view. In this report we describe the synthesis of an esterified trisuccin (referred to as trisester), and conjugation of this new derivative to MAb CC49, radiolabeling of this conjugate with rhenium-188 (188Re), and biodistribution of the labeled conjugate in athymic nude mice. Thus, trisuccin (1) was esterified with benzyl 4-hydroxybenzoate in a DCC/DMAP reaction followed by removal of all benzyl protecting groups with catalytic hydrogenation. The resulting product was conjugated to CC49 by the active ester technique, through formation of the 2-nitrophenyl ester 6, and the conjugate was radiolabeled with generator-produced 188Re. The lead molecule trisuccin 1 was also conjugated to CC49 through the active ester 5 and the conjugate was radiolabeled by the same procedure to serve as the control conjugate. Biodistributions of the labeled conjugates were studied in athymic nude mice, transplanted s.c. with LS174T human colon cancer xenografts. Although an increase in the radiolabeling yield was observed for the esterified ligand-CC49 conjugate, as well as some increase in its immunoreactivity, as compared to those for the parent trisuccin molecule, there were no significant differences in their biodistribution. This new compound therefore may be useful in improving the conjugation and radiolabeling chemistries of this trihydroxamate ligand system.
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PMID:Synthesis, rhenium-188 labeling and biodistribution studies of a phenolic ester derivative of trisuccin 1085 91

Although exposure to asbestos fibers is associated with the development of lung cancer, the underlying mechanism(s) remains unclear. Using human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells, we previously showed that UICC chrysotiles can malignantly transform these cells in a stepwise fashion before they become tumorigenic in nude mice. In the present study we used cDNA expression arrays to screen differentially expressed genes among the tumorigenic cells. A total of 15 genes were identified, 11 of which were further confirmed by northern blot. Expression levels of these genes were then determined among transformed BEP2D cells at different stages of the neoplastic process, including non-tumorigenic cells that were resistant to serum-induced terminal differentiation, early and late passage transformed BEP2D cells, five representative tumor cell lines and fused tumorigenic-control cell lines which were no longer tumorigenic. A consistent 2- to 3-fold down-regulation of the DCC (deleted in colon cancer), Ku70 and heat shock protein 27 genes were detected in all the independently generated tumor cell lines while expression levels in early transformants as well as in the fusion cell lines remained normal. In contrast, all the tumor cell lines examined demonstrated 2- to 4-fold overexpression of the insulin receptor and its signal transduction genes. Differential expression of these genes was completely restored in the fusion cell lines examined. No alteration in c-jun or EGF receptor expression was found in any of the cell lines. Our data suggest that activation of the insulin receptor pathway and inactivation of DCC and Ku70 may cooperate in malignant transformation of BEP2D cells induced by asbestos.
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PMID:Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism. 1106 61


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