Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor suppressor gene mutations in TSG101, FHIT, and PTEN/MMAC1 were found in many types of cancer and the defects in these genes are responsible for the tumor development. Since aberrant transcripts of these genes were also identified in normal tissues, the significance of these mutations in carcinogenesis has become a controversy. To determine large deletions or other alterations in these genes, we analyzed the integrity of their transcripts in both cancerous tissues and the matched normal tissues. More than 400 transcripts derived from at least eight different types of tissue were analyzed using nested RT-PCR and direct sequencing. High frequency of abnormal transcripts of all three genes occurred in both cancerous and the normal tissues. We believe that these aberrant transcripts do not relate to cancer development. These aberrant transcripts may be imperfect products of splicesome that occurs rarely but was amplified by nested RT-PCR. They may be also generated from alternative splicing due to the exonic splicing elements of the gene.
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PMID:Are aberrant transcripts of FHIT, TSG101, and PTEN/MMAC1 oncogenesis related? 1020 80

Loss of heterozygosity (LOH) is a common genetic finding in many human neoplasms, including cervical cancer. The detection of LOH at specific loci in the precursor of cervical cancer, cervical intraepithelial neoplasia (CIN) may help in elucidating the evolution of this cancer, which has a clearly defined histological premalignant phase. However, molecular genetic investigation of CIN is difficult because many of the lesions are very small and sometimes ill defined topographically. In this study we analyzed eighteen polymorphic microsatellite repeats on chromosome 3p in CINs using a method of primer extension pre-amplification (PEP) for whole genome amplification combined with microdissection. These markers encompass chromosome region 3pter-3p12. LOH at one or more loci was detected in five (33%) out of the 15 informative cases with low grade CIN (CIN 1), while 22 (92%) out of 24 cases with high grade CIN (CIN 2 and 3) (P<0.01). The highest incidence (41%) of LOH was detected at locus D3S1038 (3p26.1-3p25.2). Frequent LOH (more than 20%) was also found at other loci including D3S1110 (3p25.3-3p25.1) (31%), D3S656 (3p25.1) (24%), D3S1076 (3p21.2-3p21.1) (29%), D3S1300 (3p21.1-3p14.2) (24%), D3S1600 (3p14.2-3p14.1) (24%), and D3S1079 (3p13) (25%). The results from this study taken together with others indicate that the genetic alterations on chromosome 3p are common in high grade of CIN and are probably early events in cervical carcinogenesis. Tumor suppressor gene(s) that play a role in cervical neoplasm may be located on the short arm of chromosome 3, likely at or near 3p26.1-25.1, 3p21.2-21.1, and 3p14.2-13.
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PMID:Loss of heterozygosity at the short arm of chromosome 3 in microdissected cervical intraepithelial neoplasia. 1080 7

Pancreatic carcinogenesis is still not well characterized and no specific carcinogen has been isolated in humans. Pancreatic adenocarcinoma acquires genetic abnormalities with successive modification of genes involved in the regulation of cell proliferation and differentiation. The kinetic of genetic alterations in pancreatic cancer is not totally elucidated but experimental pancreatic cancer induced by BOP in Syrian golden hamster attempts to approach this problematic. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis regarding the detection of this mutation in preneoplastic dysplastic lesions and tumors such as intraductal mucinous papillary tumors. Tumor suppressor genes are also inactivated leading commonly to the loss of an inhibitory function on cell proliferation. This inactivation occurs with gene mutation, deletion or methylation on one chromosome arm associated with a loss of heterozygosity: it concerns p53, p16/MTS-1, DPC-4/SMAD4. We recently characterized the somatostatin receptor SST2 gene as a potential suppressor gene for pancreatic carcinoma. The kinetic of these gene alterations is unknown in human. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, NGF, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, urokinase and tissue plasminogen activators) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. Recently, the identification of human genome and the large scale analysis of transcriptoma will certainly authorize a better knowledge of pancreatic carcinogenesis as well as the identification of new genetic alterations and new clinical markers.
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PMID:[Molecular pathways of pancreatic carcinogenesis]. 1248 52

The prevention of cancer is one of the most important public health and medical practices of the 21st century. We have made much progress in this new emerging field, but so much remains to be accomplished before widespread use and practice become common place. Cancer chemoprevention encompasses the concepts of inhibition, reversal, and retardation of the cancer process. This process, called carcinogenesis, requires 20-40 years to reach the endpoint called invasive cancer. It typically follows multiple, diverse and complex pathways in a stochastic process of clonal evolution. These pathways appear amenable to inhibition, reversal or retardation at various points. We must therefore identify key pathways in the evolution of the cancer cell that can be exploited to prevent this carcinogenesis process. Basic research is identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes are active during early development and are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes are mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. Thus there is a wide range of defects in cellular machinery which can lead to evolution of the cancer phenotype. Mistakes may not have to appear in a certain order for cells to progress along the cancer pathway. To conquer this diverse disease, we must attack multiple key pathways at once for a predetermined period of time. Thus, agent combination prevention strategies are essential to decrease cancer morbidity. Furthermore, each cancer type may require custom combination of prevention strategies to be successful.
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PMID:Current mechanistic approaches to the chemoprevention of cancer. 1254 78

We report chromosome 3p deletion mapping of 32 cervical carcinoma (CC) biopsies using 26 microsatellite markers located in frequently deleted 3p regions to detect loss of heterozygosity and homozygous loss. In addition, two STS markers (NLJ-003 and NL3-001) located in the 3p21.3 telomeric (3p21.3T) and 3p21.3 centromeric (3p21.3C) regions, respectively, were used for quantitative real-time PCR as TaqMan probes. We show that quantitative real-time PCR is reliable and sensitive and allows discriminating between 0, 1 and 2 marker copies per human genome. For the first time, frequent (five of 32 cases, i.e. 15.6%) homozygous deletions were demonstrated in CCs in both 3p21.3T and 3p21.3C regions. The smallest region homozygously deleted in 3p21.3C was located between D3S1568 (CACNA2D2 gene) and D3S4604 (SEMA3F gene) and contains 17 genes previously defined as lung cancer candidate Tumor suppressor genes (TSG(s)). The smallest region homozygously deleted in 3p21.3T was flanked by D3S1298 and NL1-024 (D3S4285), excluding DLEC1 and MYD88 as candidate TSGs involved in cervical carcinogenesis. Overall, this region contains five potential candidates, namely GOLGA4, APRG1, ITGA9, HYA22 and VILL, which need to be analysed. The data showed that aberrations of either NLJ-003 or NL3-001 were detected in 29 cases (90.6%) and most likely have a synergistic effect (P<0.01). The study also demonstrated that aberrations in 3p21.3 were complex and in addition to deletions, may involve gene amplification as well. The results strongly suggest that 3p21.3T and 3p21.3C regions harbor genes involved in the origin and/or development of CCs and imply that those genes might be multiple TSG(s).
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PMID:Deletion mapping using quantitative real-time PCR identifies two distinct 3p21.3 regions affected in most cervical carcinomas. 1277 50

Tumor suppressor proteins must be exquisitely regulated since they can induce cell death while preventing cancer. For example, the p19(ARF) tumor suppressor (p14(ARF) in humans) appears to stimulate the apoptotic function of the p53 tumor suppressor to prevent lymphomagenesis and carcinogenesis induced by oncogene overexpression. Here we present a genetic approach to defining the role of p19(ARF) in regulating the apoptotic function of p53 in highly proliferating, homeostatic tissues. In contrast to our expectation, p19(ARF) did not activate the apoptotic function of p53 in lymphocytes or epithelial cells. These results demonstrate that the mechanisms that control p53 function during homeostasis differ from those that are critical for tumor suppression. Moreover, the Mdm2/p53/p19(ARF) pathway appears to exist only under very restricted conditions.
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PMID:Mdm2 regulates p53 independently of p19(ARF) in homeostatic tissues. 1467 54

It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.
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PMID:Mechanism of carcinogenesis in familial tumors. 1537 99

One of the most important medical practices of the 21st century is the chemoprevention of cancer. Much progress has been made in this new emerging field, but much work remains before widespread use and practice of cancer prevention becomes commonplace. Cancer chemoprevention includes the concepts of inhibition, reversal, and retardation of the cancer process. The process of carcinogenesis requires 20-40 years to reach invasive cancer. This process follows multiple, diverse, and complex pathways in a stochastic process, called clonal evolution. Many of these pathways appear amenable to inhibition, reversal, or retardation at various points. It is urgent that we identify key pathways in the evolution of the cancer cell, which can be exploited to prevent this carcinogenesis process. Basic researchers are identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. These precancer lesions are also called intraepithelial neoplasia (IEN). Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes, which are active during early development, are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes can become mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. These are several of a wide range of defects in cellular machinery, which can lead to evolution of the cancer phenotype. Errors may not have to appear in a defined order for cells to progress along the cancer pathway. To conquer this diverse disease, it is necessary to attack multiple key pathways at once for a predetermined period of time. Agent combination prevention strategies are, therefore, essential to decrease cancer morbidity. Each cancer type, organ location, or individual genetic background may require a custom combination of prevention strategies to be successful.
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PMID:Development of cancer chemopreventive drugs based on mechanistic approaches. 1608 17

Tumor suppressor genes play a prominent role in the modification and progression of urinary bladder carcinogenesis as a result of classic genetic alterations. Little is known about the potential significance of epigenetic events, mediated by DNA hypermethylation. This prompted our investigation to explore the global Alu methylation and the promoter methylation of the novel putative tumor suppressor genes caveolin-1 and hDAB2IP, and of p53 in transitional cell carcinomas (TCC), squamous cell carcinomas and undifferentiated small cell carcinomas of the urinary bladder. Quantitative GeneScan analysis revealed that the various histopathological tumor entities showed considerable interindividual variations in the global methylation, but the overall rate did not significantly differ between the various cancer subtypes. With methylation-specific PCR, a high frequency of methylation of the promoter region of the caveolin-1 gene was detected in undifferentiated small cell carcinomas (50%) and in squamous cell carcinomas (25.9%), while TCC were found not to be methylated. By immunohistochemistry, all squamous cell carcinomas showed a strong diffuse overexpression of caveolin-1, whereas undifferentiated small cell cancers lacked any expression. High-grade, high-stage TCC disclosed a higher incidence (60%) and a substantially stronger expression than low-grade, low-stage TCC (42.9%). Our findings suggest that hypermethylation of the caveolin-1 gene and an abnormal protein expression play a crucial role in cell differentiation, and in the phenotypical conversion of TCC into nonurothelial carcinomas. Promoter methylation of the hDAB2IP gene occurred more frequently in advanced muscle invasive (72.7%) than in superficial noninvasive (50%) TCC. DNA hypermethylation of p53 was detected in a quarter of the low-grade, low-stage TCC and undifferentiated small cell carcinomas, but only sporadically in squamous cell carcinomas, and was absent in high-grade, high-stage TCC. In conclusion, aberrant methylation and abnormal protein expression of the caveolin-1-gene is involved in the formation of nonurothelial carcinomas of the urinary bladder and promoter methylation of the hDAB2IP gene in the progression of TCC from a low to a high malignant potential.
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PMID:Transitional cell carcinomas and nonurothelial carcinomas of the urinary bladder differ in the promoter methylation status of the caveolin-1, hDAB2IP and p53 genes, but not in the global methylation of Alu elements. 1632 5

Tumor suppressor gene inactivation as proposed by the Knudson model implies a sequential inactivation of two alleles of a gene. For example, the first allele is inactivated by a missense mutation, and the second one is inactivated by a deletion or insertion. The alteration of the p53 tumor suppressor gene is far to correspond only to this model. In the great majority of cancers, the mutated allele of p53 coexists with the normal allele. It is well known that the transcriptional activity is one of the most important functions of p53. The p53 protein is active as a tetramer (this complex activates the expression of targeted genes by binding to its consensus DNA sequence called the p53 response element). Experimental evidence shows that wild-type p53 interacts with mutant proteins to form heterotetramers. In association with wild-type proteins, mutant proteins drive the wild-type subunits into a mutant conformation. This association leads to a loss of trans-activating function. The capacity of mutant subunits to form heterotetramers with wild-type subunits and to commit them into a mutant conformation is called << dominant negative effect >>. Many p53 mutant proteins possess this dominant negative activity. Recently, several factors, which are implicated in the control of the dominant negative activity of p53 mutants, have been identified. The elucidation of these complex molecular functions, which are implicated in the dominant negative activity of the p53 mutated protein represents an important aspect in the comprehension of the biological mechanisms involved in carcinogenesis.
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PMID:[Dominant negative activity of mutated p53 proteins]. 1652 13


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