Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsatellite instability (MSI) is intrinsic to most colorectal carcinomas (CRC) from patients with hereditary nonpolyposis colorectal cancer (HNPCC), reflecting germline mutations in the mismatch-repair (MMR) genes. Its occurrence and chronological sequence of development in sporadic CRC appears less well defined. To explore the time sequence in acquisition of MSI, and the role it plays during tumor progression in sporadic CRC, we compared the incidence of MSI in tissue samples from 40 Dukes'-B and 30 Dukes'-D CRC patients with liver metastases, at 4 different microsatellite loci, representing sites on the APC, DCC and p53 genes respectively as well as the D2S123 site. Among the 30 patients with hepatic metastases, MSI was found in 9 (30%) of the primary, and 13 (43.3%) of the metastatic tumors. In comparison, among the 40 Dukes'-B CRC, MSI was found in only 8 cases (20%). CRC with MSI were more frequently located in the right colon, less frequently on the left side, and seldom in the rectum. Tumor ploidy analysis shows that 46.2% of Dukes'-D primary tumors with MSI are diploid (chi2 = 4.46, p = 0.035). With a mean follow-up time of 4.2 years for the Dukes'-B CRC, there were no recurrences in the 8 patients with MSI, whilst 6 (18.8%) relapses occurred amongst the 32 patients without MSI, average time to recurrence being 15 months. In Dukes'-D CRC, mean survival time for patients with MSI was 37 months (95% CI, 24 to 51 months), for those without MSI 26 months (95% CI, 18 to 35 months), although this was not statistically significant. Our data suggest that tumor progression may involve increased genetic instability.
 ...
PMID:Microsatellite instability in sporadic-colon-cancer patients with and without liver metastases. 929 42

The mutation cluster region in the APC gene defines a region of approximately 660 bp, in which the vast majority of its somatic mutations are found. These mutations disrupt the polypeptide chain, typically eliminating five of the seven repeated sequences of 20 amino acids (aa) each in the central region of the APC protein. To examine the relationship between loss of this structure and loss of function, we constructed APC deletion mutants that progressively truncated the protein across the mutation cluster region. The mutants were tested for their association with beta-catenin and their ability to down-regulate it in SW480 cells. The binding of beta-catenin to APC fragments required the inclusion of only a single 20-aa repeat sequence, whereas down-regulation required the presence of at least three of these repeat sequences, and those including the second repeat exhibited the highest activity. The mutation of three conserved serine residues in the second repeat greatly reduced the activity of an otherwise highly active APC fragment. Thus, the repeated 20-aa sequence is directly implicated in beta-catenin turnover. The elimination of at least five of these seven repeats due to somatic mutations suggests that loss of beta-catenin regulation by APC is selected for during tumor progression.
 ...
PMID:Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. 937 78

There is vast evidence in support of the idea that accumulated genetic changes (mutations) are the underlying cause of neoplasia development. This multi-step process is aptly illustrated by colorectal carcinoma (CRC), usually developing in the course of decades, and presumably requiring at least seven genetic events to complete its development. In CRC the oncogenes most frequently undergoing mutation are c-k-ras and c-myc, and among tumor suppressant genes--APC, MCC, DCC, p53. An updated model of the molecular bases for adenoma occurrence and its evolution into carcinoma is presented. Inheritance of a single gene only which has undergone mutation augments substantially the predisposition to CRC. This is noted in a clearcut manner in the hereditary syndromes familial adenomatous polyposis (FAP) and hereditary non-polypous colorectal carcinoma (HNPCC). Recent studies along these lines suggest that the genetic defect in FAP increases the incidence of tumor initiation through functional impairment of the APC gene which is a gene regulator of the enhanced colorectal mucosa proliferation. Contrarily, the defect in HNPCC involves mainly the tumor progression through mutation of the DNA repair genes (MMRs), which are regulators of the genome stability. The study of hereditary syndromes give rise to a new concept for the occurrence and development of sporadic and inherited cancer in humans.
 ...
PMID:[The molecular biology and genetics of colorectal carcinoma]. 973 86

Aggregation of host platelets by circulating tumor cells is believed to play an important role in the metastatic process. Because thrombomodulin (TM) is one of the major mediators of the activation of the anticoagulant protein C by thrombin, we examined 136 primary tumor tissues and 45 metastatic lymph node tissues of lung squamous cell carcinomas for TM expression using immunohistochemical methods. The number of tumors with positive TM staining was less in metastatic tumors (44%) than in primary tumors (74%) (P < 0.01). Of various clinicopathological factors, better differentiation and lower N stage were significantly associated with TM expression. A loss of TM expression was associated with a shortened survival in 113 patients who underwent complete resection of the lung tumor (P < 0.01). In this group, TM expression and tumor-node-metastasis staging were independent significant determinants for survival, determined using Cox's multivariate survival analysis. Since TM is apparently associated with tumor progression and differentiation, this correlation may serve as a prognostic indicator in squamous cell carcinoma of the lung.
 ...
PMID:Prognostic value and clinicopathological correlation of thrombomodulin in squamous cell carcinoma of the human lung. 981 28

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.
 ...
PMID:Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. 985 45

During our studies of DNA fingerprinting of tumours of the pancreas and papilla (ampulla) of Vater, using arbitrarily primed polymerase chain reaction (AP-PCR), we noticed two bands showing a decreased intensity in six of ten ampullary tumours with respect to matched normal tissues. Those bands were both assigned to chromosome 5. Such a finding was somewhat in contrast with the reportedly low frequency of APC gene mutations in ampullary cancers, located at chromosome 5q21, and suggested that loci different from that of APC might be the target of chromosome 5 allelic losses (LOH) in these tumours. Therefore, we analysed chromosome 5 LOH in a panel of 27 ampullary tumours, including eight adenomas, four early- and 15 advanced-stage cancers, using 16 PCR-amplified CA microsatellite polymorphic markers spanning the entire chromosome. Nineteen cases (70%) showed LOH, and the interstitial deletions found in these tumours described two smallest common deleted regions, in which putative suppressor genes might reside. They were at 5q13.3-q14 and at 5q23-q31 respectively, which correspond to those found in gastric tumours. In addition, the presence of 5q LOH in six of eight adenomas and in three of four early-stage cancers suggests that such phenomena occur at early stages of neoplastic progression of the ampullary epithelium.
 ...
PMID:Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer. 986 79

We examined 36 cases of human sporadic colon carcinoma and corresponding normal tissue samples to evaluate loss of heterozygosity at the APC and DCC tumor suppressor genes loci using restriction fragment length polymorphism polymerase chain reaction and variable nucleotide tandem repeat analysis. Observed informativity was 83% for APC and 75% for DCC. DNA from 6 (20%) of 30 informative tumors exhibited loss of heterozygosity at the APC locus. Loss of heterozygosity at the DCC locus was observed in 7 (26%) of 27 informative tumor DNAs. Our results support the view that malignant progression is a consequence of more than one genetic change and suggest that inactivation of APC and DCC genes plays a role in a multistep process of colon tumor progression.
 ...
PMID:Loss of heterozygosity of APC and DCC tumor suppressor genes in human sporadic colon cancer. 1009 May 94

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
 ...
PMID:Colorectal cancer: molecules and populations. 1130 47

Our early work using the first array and imaging methods for the quantitative analysis of the expression of 4000 cDNA sequences suggested that modulation of mitochondrial gene expression was a factor in determining whether colonic epithelial cells displayed a differentiated or transformed phenotype. We have since dissected a pathway in which mitochondrial function is a key element in determining the probability of cells undergoing cell-cycle arrest, lineage-specific differentiation, and cell death. Moreover, this pathway is linked to signaling through beta-catenin-Tcf, but in a manner that is independent of effects of the APC gene on beta-catenin-Tcf activity. Utilization of unique mouse genetic models of intestinal tumorigenesis has confirmed that mitochondrial function is an important element in generation of apoptotic cells in the colon in vivo and has demonstrated that modulation of cell death may be involved in intestinal tumor progression rather than initiation. Normal spatial and temporal patterns of cell proliferation, differentiation, and apoptosis in the colonic mucosa are determined by developmentally programmed genetic signals and external signals generated by homo- and heterotypic cell interactions, humoral agents, and lumenal contents. Mitochondrial function may play a pivotal role in integrating these signals and in determining probability of cells entering different maturation pathways. How this is accomplished is under investigation using high-density cDNA microarrays.
 ...
PMID:Cellular mechanisms of risk and transformation. 1066 79

Like sporadic colorectal cancers, ulcerative colitis (UC)-related cancers are thought to evolve through a multistep progression pathway. The genomic alterations important in sporadic colorectal carcinogenesis are well characterized, with loss of APC function being a frequent and early event. However, the genomic alterations in UC-related carcinogenesis are yet unclear and the role of APC is controversial. In this study genomic alterations in UC-related cancers, dysplasias and nondysplasias were assessed by comparative genomic hybridization (CGH). Alterations of the APC/beta-catenin pathway were evaluated by immunohistochemistry. 32 cases of UC-related cancers (14 with synchronous dysplasias and nondysplasias) and 42 sporadic cancers were matched by UICC stage. CGH was performed using DOP-PCR amplification after microdissection. Expression of beta-catenin, E-cadherin and APC were detected by immunohistochemistry in paraffin sections. Chromosomal alterations were present in 90% of the sporadic and 94% of the UC-related cancers. 86% of the UC-related dysplasias and 36% of the nondysplasias showed changes by CGH. Chromosome 5q was lost in 56% of UC-related cancers and 36% of the dysplasias but in only 26% of the sporadic cancers. Other frequent alterations in both cancer groups were loss of 18q, 8p, 17p, and gain of 8q and 20q. Immunohistochemistry showed a decrease of membranous and an increase of cytoplasmic expression of E-cadherin and beta-catenin in UC-related and sporadic cancers. APC expression was significantly decreased in both tumor types. Clonal chromosomal alterations occur early in UC-related tumor progression. UC-related and sporadic cancers share a set of common clonal abnormalities. The frequent loss of 5q and the altered expression of APC, beta-catenin, and E-cadherin proteins in UC-related cancers indicate a critical role of the APC/beta-catenin pathway in UC-related carcinogenesis.
 ...
PMID:[Molecular carcinogenesis in ulcerative colitis-associated and sporadic colorectal carcinoma--differences and similarities]. 1071 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>