Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are abnormalities in the structure and/or function of several oncogenes and growth factors in human pancreatic cancer, notably the EGF receptor and its ligand TGF alpha, c-erb B-2 proto-oncogene, Ki-ras oncogene and the tumour suppressor gene p53. The temporal sequence of their activation and the nature of the aetiological agents responsible for their activation are not yet clear. In vitro pancreatic culture systems and transgenic animal experiments are needed to reconstruct and define those molecular events that are necessary and sufficient for the neoplastic phenotype.
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PMID:Growth factors and oncogenes in pancreatic cancer. 196 2

Abnormalities affecting tumour suppressor genes on chromosome 5q21 are increasingly recognised as important in the pathogenesis of a variety of human cancers, particularly of the gastrointestinal tract. We have examined a series of gastric and pancreatic cancers from European patients for loss of heterozygosity (LOH) of markers within and around the APC and MCC genes on chromosome 5q21 using restriction fragment length polymorphism and polymerase chain reaction techniques. We find that LOH of the APC and MCC genes is particularly frequent in gastric cancers of diffuse type, but very infrequent in pancreatic cancers. We have also used single-strand conformational polymorphism to screen for abnormalities of the sequence of the APC and MCC genes in a panel of pancreatic cancer cell lines. Our results suggest that there are distinct differences in the molecular pathogenesis of gastric and pancreatic cancer and that abnormalities of APC and MCC may be involved particularly in the diffuse type of gastric cancer.
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PMID:Abnormalities affecting the APC and MCC tumour suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer. 840 87

Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.
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PMID:Low incidence of BRCA2 mutations in breast carcinoma and other cancers. 864 Feb 36

DNA fingerprinting can be used to detect genetic rearrangements in cancer that may be associated with activation of oncogenes and inactivation of tumour suppressor genes. We have developed a fingerprinting strategy based on polymerase chain reaction (PCR) amplification of genomic DNA with primers specific for the Alu repeat sequences, which are highly abundant in the human genome. This has been applied to DNA from pancreatic cancer and paired normal samples to isolate and identify fragments of genomic DNA rearranged in the malignant cells. These fragments have been sequenced and used as probes to isolate hybridising clones from gridded bacteriophage P1, phage artificial chromosome, and cosmid libraries for fluorescent in situ hybridisation mapping and the identification of expressed sequences. Further characterisation has identified a putative novel gene (ART1) that is up-regulated specifically in pancreatic cancer as well as another sequence with similarity to genes involved in differentiation (POU domains). In conclusion, we suggest that Alu-PCR fingerprinting may be a useful technique for the identification of genes involved in tumourigenesis.
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PMID:Alu-polymerase chain reaction genomic fingerprinting technique identifies multiple genetic loci associated with pancreatic tumourigenesis. 899 78

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.
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PMID:Molecular advances in pancreatic cancer. 943 1

Our understanding of the molecular pathology underlying the development and progression of ductal pancreatic cancer has been revolutionised during the last 5 years due to the spectacular development of novel molecular biological techniques. In the present article, we describe key molecular alterations of sporadic and inherited ductal pancreatic cancer. Overexpression of growth factors and growth factor receptors are present in a significant proportion of this tumour type. Mutation of the K-ras oncogene, and disruption of p53 or p16 tumour suppressor gene abrogates the control of the cyclin-dependent kinases (cdk) and retinoblastoma (Rb) gene pathway, causing continuous growth of the pancreatic tumour. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor beta signalling pathway. Lost or decreased expression of retinoid receptors and failure of telomerase activity may play a role in pancreatic carcinogenesis. Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis. Furthermore, the cytogenetic changes in this cancer are summarised. This molecular pattern distinguishes pancreatic cancer from other epithelial tumours and represents a promising basis for the development of diagnostic and other clinical applications.
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PMID:Molecular pattern of ductal pancreatic cancer. 964 82

Chromosomal abnormalities, including mutations, deletions and allelic losses of different oncogenes and tumour suppressor genes have been discovered in the DNA of cancer cells and the application of molecular biological techniques now permits identification of these alterations in tumours. Although it has been possible to detect potentially important genetic alterations in tumour material for some years, it is now evident that many neoplasms shed tumour cells into sputum, urine, bile, pancreatic juice, faeces and blood of infected patients. Mutated DNA has also been detected free in the plasma of patients with cancer, and the DNA alternations in plasma are identical to those in the DNA of the primary cancer cells. Thus, the identification of DNA mutations in plasma, pancreatic juice and faeces might be a useful approach for the early detection and monitoring of patients with pancreatic cancer. The K-ras gene is mutated in over 90% of pancreatic cancer. These mutations are well defined, reliably detected by DNA application in assays and occur early in the genesis of pancreatic cancer. K-ras mutations can be detected in cancer tissue and pancreatic duct secretions. K-ras mutations have also been detected in stool of patients with pancreatic cancer. Invasive techniques for obtaining pancreatic juice or pancreatic tissue are undesirable and would certainly be inappropriate for cancer screening. Similarly, there is a lack of enthusiasm for developing diagnostic techniques that involve faecal extractions. Isolation of plasma DNA from pancreatic patients and detection of K-ras alterations with a PCR assay and subsequent product sequencing showed K-ras mutations in the plasma of 17 out of 21 patients (81%), and in cases in which both plasma and pancreatic tissue were available, DNA mutations were similar in plasma and tissue. Plasma DNA alterations were found 5-14 months before the clinical diagnosis of pancreatic cancer in 4 patients. K-ras mutations are also demonstrated in micro-dissected tissues taken from patients with pancreatic hyperplasia, with or without chronic pancreatitis. This has lead to the suggestion that pancreatic cell hyperplasia may be a premalignant condition although the demonstration of K-ras alterations in some cases of chronic pancreatitis has raised doubts about the sensitivity and specificity of K-ras testing for pancreatic cancer. However, the detection of K-ras mutations in plasma may still identify patients with or at risk of developing pancreatic cancer as it may only be in these patients that sufficient quantities of mutated DNA enter and can be detected in plasma. Thus, this non-invasive approach to early cancer detection may be applicable both to diagnosis of the symptomatic patient and for screening. A combined approach with other tumour markers such as p53 gene might increase the sensitivity of the test.
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PMID:Diagnosis of pancreatico-biliary malignancy: detection of gene mutations in plasma and stool. 1043

Carcinoma of the pancreas has a grim prognosis even following surgical resection. Only a relatively small proportion of patients have a resectable tumour at presentation. At the present time it is uncertain whether the use of radical forms of surgery, or adjuvant therapy improve survival. It is however unlikely that either of these approaches will greatly increase the number of long term survivors. Earlier diagnosis particularly in individuals who are at greater risk of developing carcinoma of the pancreas is one way in which results might be improved. Unfortunately current imaging techniques are inadequate for the diagnosis of early disease. New molecular diagnostics techniques that can identify example mutations in oncogenes such as K-ras or deletions of tumour suppressor genes such as P53 or P16 are being developed. These tumour specific abnormalities are also a target for gene therapy. Surgery alone cannot cure any patient with pancreatic cancer but may in the future in conjunction with these new approaches.
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PMID:The future of surgery for pancreatic cancer. 1043 42

Small amounts of free DNA circulate in both healthy and diseased human plasma/serum, and increased concentrations of DNA are present in the plasma of cancer patients. Characteristics of tumour DNA have been found in genetic material extracted from the plasma of cancer patients. These features include decreased strand stability and the presence of specific oncogene, tumour suppressor gene and microsatellite alterations. Point mutations of the ras genes have been detected in the plasma DNA of patients suffering from haematopoetic malignancies, colorectal and pancreatic cancer, sometimes prior to clinical diagnosis. Rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkins lymphoma and acute B cell leukaemia. Microsatellite instability, expressed either as a new allele or a loss of one allele (LOH) occurs in the plasma and serum DNA of patients suffering from head and neck, lung and renal cell cancer. The results obtained in many different cancers have opened a new research area indicating that plasma DNA might eventually be a suitable target for the development of non-invasive diagnostic, prognostic and follow-up tests for cancer.
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PMID:Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. 1050 46

Pancreatic cancer represents the fourth leading cause of cancer death in men and the fifth in women. Prognosis remains dismal, mainly because the diagnosis is made late in the clinical course of the disease. The need to improve the diagnosis, detection, and treatment of pancreatic cancer is great. It is in this type of cancer, in which the mortality is so great and the clinical detection so difficult that the recent advances of molecular biology may have a significant impact. Genetic alterations can be detected at different levels. These alterations include oncogene mutations (most commonly, K-ras mutations, which occur in 75% to more than 95% of pancreatic cancer tissues), tumour suppressor genes alterations (mainly, p53, p16, DCC, etc.), overexpression of growth factors (such as EGF, TGF alpha, TGF beta 1-3, aFGF, bTGF, etc.) and their receptors (i.e., EGF receptor, TGF beta receptor I-III, etc.). Insights into the molecular genetics of pancreatic carcinogenesis are beginning to form a genetic model for pancreatic cancer and its precursors. These improvements in our understanding of the molecular biology of pancreatic cancer are not simply of research interest, but may have clinical implications, such as risk assessment, early diagnosis, treatment, and prognosis evaluation.
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PMID:Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective. 1066 Apr 90


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