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

Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33-55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential 'hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI.
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PMID:Renal cell carcinomas in trichloroethene (TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene. 913 12

Allelic imbalance or loss of heterozygosity (LOH) studies have been used extensively to identify regions on chromosomes that may contain putative tumour suppressor genes. We looked for evidence of microsatellite instability (MI) and LOH on chromosome 7q, 10q, 11p and 17q using seven polymorphic microsatellite markers. In 42 paired breast cancer-peripheral blood DNA samples we identified 24 tumours (57%) exhibiting genetic alterations. Twenty-one specimens exhibited LOH (50%), while 11 specimens exhibited MI (26%) in at least one microsatellite marker. The most frequent incidence of LOH was found for the marker THRA1 (8/33, 24%) indicating that thra I gene becomes a strong candidate tumour suppressor gene, whereas of MI it was D10S109 (3/26, 12%). These MI and LOH data were analysed using a range of clinicopathological parameters. Tumours displaying MI with no evidence of LOH and tumours exhibiting MI and LOH belonging to stage II or III were found, however none were at stage I. These data suggest that MI may be an early event in mammary tumorigenesis whereas LOH occurs at a late stage. A significant association between the absence of oestrogen receptors (p < 0.01) and the absence of both oestrogen and progesterone receptors (p < 0.001) at 17q21 were observed, indicating a possible relationship between specific genetic changes at this region and hormonal deregulation in the progression of breast cancer.
Tumour Biol 1997
PMID:Microsatellite instability and loss of heterozygosity in primary breast tumours. 914 12

Apoptosis is a process of single-cell deletion requiring active participation of the cell in its own demise. First described in 1972, it is now known to play a major role in embryogenesis, tissue homeostasis and neoplasia. Apoptosis can be initiated when DNA damage occurs causing the cell to pause in its reproductive cycle. If the DNA damage is beyond repair, the cell proceeds to apoptotic cell death. When the genetic mechanism(s) involved in the pathway of apoptosis is altered, the cell does not die. Further mutations occur by proliferation and such multiple mutational events can lead to a malignant phenotype and cancer growth. The tumour suppressor gene p53 causes a DNA-damaged cell to rest and attempt repair. If damage is irreparable, p53 levels will continue to increase, initiating apoptosis. Mutation of p53, found in approximately 50% of cancers, can stop the apoptotic process. Increased bcl-2 expression, an apoptosis inhibitor, also plays a role in cellular transformation and cancer growth. Its altered expression occurs in the presence of oncogene expression. This paper reviews the role of apoptosis in malignant transformation, cancer growth, and response to therapy for gynaecological cancers. For cervical cancer and its precursors, data on apoptotic index, bcl-2 and Bax expression are presented and discussed in relationship to human papillomavirus expression. In ovarian epithelial malignancies, the role that apoptosis plays in chemotherapeutic responses is reviewed. The data for endometrial cancer are currently limited to apoptotic index.
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PMID:The role of apoptosis in gynaecological malignancies. 918 26

Two forms of neurofibromatosis, type 1 (NF1) and type 2 (NF2) are connected with genes localized on chromosomes 17 and 22, respectively. The genes that are inactivated in neurofibromatosis code for the proteins neurofibromine and merline, respectively. Since inactivation leads to neoplasia, they are called tumour suppressor genes. Neurofibromine shows resemblances to proteins that serve to inactivate oncogenes. Merline has a relationship with proteins that connect the cytoskeleton and the cell membrane. The precise function of the proteins is still unknown. The NF1 gene is characterized by extraordinarily high sensitivity to mutation; half the NF1 patients have not inherited the disease. In the familial form of neurofibromatosis, a mutated gene is inherited and the normal allele in the tumour is inactivated, making tumour growth possible. In the sporadic form of neurofibromatosis, both normal alleles are inactivated locally in the tissue so that a tumour develops in that place.
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PMID:[Molecular-genetic aspects of neurofibromatosis]. 919 May 37

Cytogenetic techniques for the analysis of genetic changes common in head and neck squamous cell carcinogenesis show complex patterns of chromosomal deletions, translocations, and amplifications. Powerful molecular biologic techniques have recently made possible the investigation of these abnormalities at the DNA level. Tumour suppressor gene loss and oncogene activation can now be recognized in tumours. Multiple genetic loci are implicated in the carcinogenesis process, while much evidence points to the existence of yet to be recognized tumour suppressor genes. An overview of the genetic changes commonly seen in head and neck squamous cell carcinogenesis and the possible implications of these are presented.
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PMID:Biologic implications of genetic changes in head and neck squamous cell carcinogenesis. 923 4

Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.
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PMID:Somatic mutation of the MEN1 gene in parathyroid tumours. 924 Dec 76

Inactivation of tumour suppressor gene function is a critical step in the development of human neoplasia. The Rb and CDKN2 tumour suppressor genes are inactivated in many tumour types, including the late stages of prostate cancer, and appear to function in the same suppressor pathway. p53, another major tumour suppressor is also mutated in a subset of advanced-stage prostate carcinomas. E-cadherin and other cell adhesion genes, which have been characterized as suppressors of the metastatic phenotype, are inactivated or downregulated during progression to advanced prostate cancer and have been associated with poor clinical outcome. The early genetic events involved a prostatic neoplasia are poorly understood, but loss of as yet undiscovered tumour suppressor genes may play a role in the initiation of this disease.
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PMID:Tumour suppressor genes in prostate cancer. 929 77

Within the past 15 years a new family of peptides has been identified, known as trefoil factor family (TFF) domain peptides; they are associated with mucin-secreting epithelial cells and synthesised predominantly in the gastrointestinal tract. They share a highly conserved physical structure, and their role in mucosal defence and healing is becoming increasingly clear, more recently a tumour suppressor function has been postulated. Outside the gastrointestinal tract, members of this group of peptides have also been identified in the normal hypothalamus and pituitary, and in normal breast tissue where it is responsive to oestrogen stimulation. Evidence of peptide expression has been found in a range of urological, gynaecological, gastrointestinal, pulmonary and breast carcinomas, and in the last two it appears to carry prognostic significance. The present review aims to summarise the rapidly expanding data on the role of these peptides in epithelial inflammation, repair and neoplasia.
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PMID:Trefoil factor family domain peptides. 946 69

Cytogenetic and molecular analysis of soft tissue tumours has yielded a wealth of new information over the past 10-15 years. Many soft tissue neoplasms show specific karyotypic aberrations which have proved to be diagnostically valuable, and have also assisted in the understanding of pathogenetic mechanisms and rationalisation of classification systems (e.g. lipomatous tumours and Ewing's sarcoma/PNET). In certain clinical subsets, especially round cell sarcomas and fatty neoplasms, determination of karyotype (whether by conventional analysis, FISH or RT-PCR) has proved often to be useful in the diagnostic setting. Additionally the recognition of clonal abnormalities in both benign neoplasms as well as lesions formerly thought to be non-neoplastic (e.g. inflammatory "pseudotumour") has prompted reassessment of biologic concepts with regard to growth control. Inherited molecular genetic defects which predispose to soft tissue neoplasia (e.g. NF-1, Li-Fraumeni syndrome) have been characterised, leading to a greater understanding of tumour suppressor genes. Mesenchymal differentiation genes, the modes of action of which may help to expunge concepts of histogenesis, are being characterised. It is becoming clear that there exist growth control genes (such as the HMGI family) which, irrespective of differentiation, play an important role in a wide range of different mesenchymal tumours. Additionally it is evident that different histologic types of sarcoma (e.g. variants of liposarcoma) show quite different abnormalities of cell cycle control (notably at the G1-S checkpoint) and it seems increasingly likely that certain genetic aberrations, identifiable either at the chromosomal or individual gene level, may prove to be of prognostic relevance in sarcomas and may also open novel therapeutic avenues. While the validity of all molecular genetic data depends totally on skilled histological diagnosis and grading, there has never been a better time for close collaboration between pathologists and basic scientists in the study of soft tissue neoplasia.
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PMID:Soft tissue tumours: the impact of cytogenetics and molecular genetics. 947 86

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


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