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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial aggregations of defined malignancies are of great importance for determining the genetic factors involved, as has been demonstrated for familial and sporadic retinoblastoma. In nearly all organs, neoplasms occur that are inherited similar to familial retinoblastoma (Rb). For example, more than 5% of all women suffering from breast cancer belong to breast cancer families in which the occurrence of the malignancy suggests an autosomal dominant pattern of inheritance. Familial colon cancer is associated with several well-known autosomal dominantly inherited polyposis syndromes, and also other susceptibilities without obvious clinical features. Site-specific cancers are often accompanied by other malignancies. In addition, there seem to be predispositions to a wider range of different, but well-defined neoplasms: e.g., adenocarcinomatosis of the colon and the endometrium, or the Li-Fraumeni/SBLA syndrome. The latter shows a spectrum of sarcoma, brain tumours, breast cancer, leukaemias, lung and adenocortical cancer. The genes leading to these types of dominantly inherited predispositions appear to be the tentatively so-called tumour suppressor genes, for which the Rb gene serves as a model. It manifests itself recessively on the level of the individual cell, which means both alleles must be deleted or inactivated before a retinoblast develops into a neoplastic cell. Clinical, epidemiological and molecular genetic studies have yet to establish whether the Rb model can be extended to all other forms of dominantly inherited human cancers.
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PMID:Dominant inheritance in human cancer. 219 May 28

The genetic factors involved in the multistep process of carcinogenesis can be divided at least into two major categories: 1. Mutated or lost genes, which may directly represent one step in the sequential process (tumour suppressor genes); inheritance of one tumour suppressor gene causes dominant expression of the carcinogenic phenotype (the dominant inheritance is described in the accompanying paper); 2. Other genes, which lead to conditions that favour the development of cancer and generally are inherited in a recessive fashion; they are the subject of this paper. Autosomal recessively inherited diseases, such as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's anaemia display increased genome instability (chromosomal fragility and/or DNA-repair deficiencies) and are associated in the homozygote and probably also in the heterozygote state with defined malignancies. Neoplasms particularly of the lymphoreticular system frequently occur in patients with genetically determined immunodeficiencies (e.g. severe combined immune deficiency or Wiskott-Aldrich syndrome). People differ due to their individual genetic constitution in their responses to various classes of carcinogens such as physical and chemical agents, to dietary habits, as well as to viruses. Furthermore, tumours are often found in patients displaying premature aging (e.g. Werner's syndrome). In addition, several metabolic abnormalities such as genetic syndromes featuring chronic liver disease, but also many other inherited metabolic conditions have cancer as a regular or frequent complication.
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PMID:Recessively inherited deficiencies predisposing to cancer. 219 May 29

The p53 gene has been a constant source of fascination since its discovery nearly a decade ago. Originally considered to be an oncogene, several convergent lines of research have indicated that the wild-type gene product actually functions as a tumour suppressor gene. For example, expression of the neoplastic phenotype is inhibited, rather than promoted, when rat cells are transfected with the murine wild-type p53 gene together with mutant p53 genes and/or other oncogenes. Moreover, in human tumours, the short arm of chromosome 17 is often deleted. In colorectal cancers, the smallest common region of deletion is centred at 17p13.1; this region harbours the p53 gene, and in two tumours examined in detail, the remaining (non-deleted) p53 alleles were found to contain mutations. This result was provocative because allelic deletion coupled with mutation of the remaining allele is a theoretical hallmark of tumour-suppressor genes. In the present report, we have attempted to determine the generality of this observation; that is, whether tumours with allelic deletions of chromosome 17p contain mutant p53 genes in the allele that is retained. Our results suggest that (1) most tumours with such allelic deletions contain p53 point mutations resulting in amino-acid substitutions, (2) such mutations are not confined to tumours with allelic deletion, but also occur in at least some tumours that have retained both parental 17p alleles, and (3) p53 gene mutations are clustered in four 'hot-spots' which exactly coincide with the four most highly conserved regions of the gene. These results suggest that p53 mutations play a role in the development of many common human malignancies.
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PMID:Mutations in the p53 gene occur in diverse human tumour types. 253 45

This investigation of oral squamous carcinoma in five individuals revealed that four of the patients were constitutionally heterozygous at the c-Ha-ras-1 locus and that the tumour from one patient had lost that heterozygosity. The loss of c-Ha-ras-1 alleles provides a useful marker for detecting deletions of genetic material located on the short arm of chromosome 11 (11p) and has been found in association with a number of malignant tumours but has not been previously described in carcinoma of the head and neck. The repeated association of 11p deletions with malignancies has led to the postulation of a recessive cancer gene or tumour suppressor gene at this location involved in carcinogenesis and tumour progression. This study indicates that such a mechanism may contribute to the development of oral squamous carcinoma.
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PMID:Loss of Harvey ras heterozygosity in oral squamous carcinoma. 256 83

The study of hereditary cancer in humans, notably retinoblastoma, has identified a category of cancer genes that is different from that of the oncogenes. Whereas the latter group of genes exerts its effect through expression, the former does so as a result of failure of normal expression. Primary oncogene abnormality seems to play a crucial initiating role in certain neoplasms, particularly leukaemias, lymphomas and some sarcomas. In contrast, anti-oncogenes (tumour suppressor genes) appear to be important in the initiation of several solid tumours of children, as well as some common carcinomas of adults. Both classes are apparently involved in tumour progression and metastasis. Virtually every kind of cancer can occur in hereditary form, so the role of anti-oncogenes in the origin of human cancers may be considerable. The prototypic anti-oncogene has been that for retinoblastoma. For this tumour the recessive mechanism has been demonstrated by molecular means, and the gene has been cloned. The possibility has been suggested that gene (or gene product) replacement therapy could be accomplished.
Br J Cancer 1989 May
PMID:The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers: clues to mechanisms of carcinogenesis. 266 Aug 94

Genetic tumours of Xiphophorus are one of the classical experimental models that underline the concept that cancers develop as a result of abnormal gene expression. Formal genetics has indicated that cancer development in Xiphophorus starts when oncogenes are expressed abnormally due to elimination of tumour suppressor genes. The suppressor gene Diff seems to suppress malignancy by controlling terminal differentiation of cells. It appears now that control of terminal differentiation may also be one of the properties of human tumour suppressor loci, in particular the Rb gene. Although it is difficult at this point to envision which molecular or biochemical function of tumour suppressor genes we might be able to identify, research on tumour suppression will at least allow another glimpse at how basic mechanisms of cell differentiation and multiplication operate. It is not clear, however, if elimination of tumour suppressor genes alone is sufficient to elicit the fully malignant phenotype. Cytogenetic studies have shown various nonrandom chromosomal abnormalities in those human tumours in which elimination of a tumour suppressor gene seems to be a critical step in tumorigenesis. In Xiphophorus, it is obvious from our molecular studies that additional genetic events can contribute to the malignant phenotype. Of these, amplification of cellular DNA may have a role in malignant progression of melanomas. At this point, the exact contribution of amplification to genetic melanoma is unclear. Judging from the role of amplification in human and murine tumours, the significance of amplification, in addition to suppressor elimination, in melanomas of Xiphophorus is likely to be high.
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PMID:Genetic suppression of malignancy. 268 Sep 48

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.
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PMID:Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. 289 13

Somatic cell hybrids were produced by fusion of normal human (foreskin) fibroblasts and a transformed Chinese hamster fibroblast line V79-8. Overall, approximately 30% of hybrid clones showed stable reversion to normal morphology and growth control in vitro as shown by serum and anchorage dependence. In one-third of these clones, senescence was observed after a number of generations similar to that required for the human fibroblast parent cells to senesce. The remainder appear to be immortal. Normal human chromosomes can therefore restore growth control with or without finite life-span to this transformed cell. V79 cells were found to be transfectable at an efficiency compatible with detection of single-copy gene transfer from genomic DNA. Furthermore, these cells were exceptionally sensitive to negative ("suicide") selection. Taken together, our data suggest that the V79 line represents an ideal system for isolation of human tumour suppressor genes.
Int J Cancer 1989 Feb 15
PMID:Suppression of transformation and immortality in human/Chinese hamster fibroblast hybrids--a model for suppressor gene isolation. 291 3

Liver cancer is one of the most prevalent forms of cancer in the world. Hepatitis B virus (HBV) is considered to be a major aetiological factor. Evidence from epidemiological studies has also indicated that environmental contaminants such as mycotoxins may, either in combination with HBV or independently, be important aetiological factors in the pathogenesis of primary hepatocellular carcinoma (PHC). Laboratory data also suggest an interplay between viral and chemical factors in the multifactorial aetiology of PHC. Aflatoxin B1, the chemical carcinogen most frequently implicated in the aetiology of hepatocellular carcinoma is a procarcinogen that must be activated by mixed-function oxidases to an electrophilic metabolite before it can exert its carcinogenic effects. Interindividual differences (greater than 10-fold) in the metabolic activation of aflatoxin B1 are observed. These differences may play a part in an individual's oncogenic susceptibility to aflatoxin B1. Chemical carcinogens and integrated HBV may activate cellular oncogenes, eg N-ras, and inactivate tumour suppressor genes. Recently developed methods that allow monitoring of aflatoxin B1 and HBV exposures and also genetic damage caused by these agents in individuals should help in biochemical and molecular epidemiological studies concerning the aetiology of hepatocellular carcinoma. We identify areas of uncertainties and of future experimentation and propose a hypothesis of liver carcinogenesis.
Cancer Surv 1986
PMID:Interactive effects of chemical carcinogens and hepatitis B virus in the pathogenesis of hepatocellular carcinoma. 304 Feb 43

In a study of DNAs from 100 breast cancer patients and 100 controls, there were no differences in the frequencies of common or rare alleles at the Harvey ras (c-Ha-ras) locus on chromosome 11. However, one Ha-ras allele was deleted from the tumour DNA in 14 of 65 informative patients. Loss of a Ha-ras allele correlates with paucity of oestrogen receptor protein and with increased tumour size at presentation, but is not associated with microscopic evidence of lymph node invasion. The findings on Ha-ras and other informative loci are consistent with the possibility that a tumour suppressor gene involved in the early stages of breast cancer is located on the short arm of chromosome 11.
Br J Cancer 1988 Dec
PMID:Partial deletion of chromosome 11p in breast cancer correlates with size of primary tumour and oestrogen receptor level. 306 95


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