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)

In hereditary cancers the responsible inherited cancer genes are defective (mutated) anti-oncogenes (tumour suppressor genes). This inherited mutation is present in all cells of the organism, and only leads to cancer if in a somatic cell a complete set of specific cancer mutations is accumulated. Since one defective anti-oncogene has been inherited, only three additional somatic cancer mutations are required, according to our previously published view (Anticancer Res 10:1990). The number of de novo arising tumour cells in such a person is thus multiplied by a factor equal to the reverse of the mutant frequency, that is about 10(4)-10(5). This can be observed e.g. in retinoblastoma. Mutations occur in proliferating cells only. Consequently cancer mutations also depend on cell proliferation. If an inherited cancer mutation predisposes to cancer formation in certain organs, then the cancer risk in these organs is enhanced by 10(4)-10(5) times. Tumours in these organs will appear simultaneously if the number of cells and the growth kinetics are similar. This is of course observed in paired organs, like the retina and the female breast. In cancer family syndromes different organs may be affected at the same time. Examples are type I and type II cancer family syndrome and multiple endocrine neoplasia type 1 2a, and 2b. The secondly diagnosed tumours are not caused by metastatic spread. Tumours in two organs will arise at difference times if the number of end cells per organ and the growth kinetics differ. In this case the second tumour is called a second primary malignancy and is not caused by metastatic spread. A good example are the second primary malignancies in hereditary retinoblastoma. The inherited defective anti-oncogene is a recessive gene. This defective inherited gene causes a 10(4)-10(5) fold increase of the normal tumour incidence. This means that nearly always one or more tumours will arise. Evidently, this pattern of inheritance has led to the erroneous conclusion that the genetic abnormality is dominant at the level of the chromosome. The 10(4)-10(5) times enhanced tumour incidence in hereditary cancer is helpful for the clinical recognition of hereditary cancer. That is, hereditary cancer can be recognized not only by family history, but also by early occurrence, the multifocal and bilateral localisation, its occurrence as cancer family syndrome or by second primary malignancies. It is thus recommended to screen patients and families with hereditary cancer for first and second primary tumours. Treatment of patients with hereditary tumours requires extra care to avoid additional cancer mutations.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hereditary cancer and its clinical implications: a view. 219 May 27

Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.
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PMID:Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2. 768 2

The tumorigenesis of neuroendocrine tumours remains poorly understood, although a minority, the familial multiple endocrine neoplasia (MEN 1 and MEN 2), are known to be of uncommon genetic origin. Mutation of the tumour suppressor gene, p53, is now known to be a common genetic alteration in about half of all types of non-endocrine cancers. In the present study, immunocytochemistry using the monoclonal anti-p53 antibody, DO-7, has been employed to investigate the accumulation of p53 immunoreactivity in a wide range of primary neuroendocrine tumours. Tumours (n = 109) were fixed and processed to paraffin wax according to a constant protocol. Sections were subjected to microwave antigen retrieval prior to immunostaining for p53. Positive nuclear immunostaining was observed in one medullary carcinoma of the thyroid (MCT), one lung carcinoid, and five small cell carcinomas of the lung (SCCL). All other tumour samples were consistently negative. As the neoplasia investigated in this study comprised a wide spectrum of neuroendocrine tumour types and ranged from minute, relatively benign lesions to malignant metastasizing disease and as there was no relationship between the presence of p53 overexpression and clinico-pathological features, the present study suggests that p53 gene mutation may be relatively unimportant in the genesis of neuroendocrine tumours.
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PMID:Overexpression of the tumour suppressor gene p53 is not implicated in neuroendocrine tumour carcinogenesis. 877 44

Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction.
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PMID:The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumours. 784 1

The syndrome of multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour disease of the neuroendocrine system with manifestations in the parathyroids, pancreas, duodenum and pituitary gland and rarely also in the stomach and thymus. Recently, the MEN 1 gene locus has been mapped to the long arm of chromosome 11. This gene most likely belongs to the tumour suppressor genes, the allelic loss of which causes tumour development. The pancreatic and duodenal tumours may metastasize, but usually have a low malignant potential. Clinically, most MEN 1 patients present between the age of 20 and 35 with hyperparathyroidism and/or Zollinger-Ellison syndrome.
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PMID:[Multiple endocrine neoplasia type 1 (MEN 1). Molecular genetics, morphology and prognosis]. 791 16

Multiple endocrine neoplasia type 1 is an autosomal dominantly inherited disorder predisposing to development of neoplastic lesions in the parathyroid glands, the neuro-endocrine pancreas-duodenum and the anterior pituitary. The genetic defect was mapped to the centromeric region of the long arm of chromosome 11, based on studies of somatic deletions in MEN 1-associated tumours and linkage analysis in affected families. Combined family and tumour analyses have shown that tumourigenesis in MEN 1 involves loss of the wild type chromosome, indicating that the putative MEN 1 gene is a tumour suppressor gene. Based on results from linkage analysis in more than 40 MEN 1 families, presymptomatic testing for MEN 1 using DNA polymorphisms can now be performed with high accuracy. Hence, biochemical screening programmes can focus on individuals at risk, in order to identify early signs of tumour development.
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PMID:Family screening in multiple endocrine neoplasia type 1 (MEN 1). 791 25

The 11q13 chromosomal region encodes oncogenes relevant to a variety of human cancers as well as a tumour suppressor gene implicated in multiple endocrine neoplasia type 1. In addition, high affinity folate receptor (FOLR1), which maps to 11q13.3-13.5, is expressed at an elevated level on the surface of over 80% of nonmucinous epithelial ovarian cancers. Further telomeric, 11q breakpoints are found in many cancers. We studied the involvement of 11q markers in ovarian cancer by looking for tumour-specific loss of heterozygosity (LOH), as well as amplification or rearrangements that might explain the overexpression of FOLR1. Twenty eight epithelial ovarian cancers, along with lymphocyte DNA from the same individual were used for Southern blotting with polymorphic probes from 11q. PCR primers from 11q23.3 were also used. The 11q13 band was amplified in four out of 28 cancers. The amplicon included the probe D11S146 as well as FGF3 (formerly INT2) and FOLR1 in one out of these four cases, thus crossing the bcl1 translocation breakpoint. LOH was seen in three out of 16 cases with FGF3 (11q13). A much higher frequency of LOH (8/12) was found at 11q23.3-qter, implying the presence of a tumour suppressor gene in this region.
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PMID:Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer. 809 91

The FAU gene (FBR-MuSV associated ubiquitously expressed gene) encodes the ribosomal protein S30 fused with a Ubiquitin-like molecule. The FAU gene is expressed in a wide range of tissues, is evolutionarily conserved, and has putative tumour suppressor activity in vitro. The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus. This locus is tightly linked to the Multiple Endocrine Neoplasia type 1 (MEN1) locus. The FAU gene properties, together with its chromosomal localisation on 11q13, make it a candidate gene for MEN1. To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data. Furthermore, 10 parathyroid and pancreatic tumours from MEN1 patients and 15 each of sporadic parathyroid and pituitary tumours were similarly examined. In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis. No FAU gene anomalies could be demonstrated by any of these techniques. We conclude that FAU is not likely to be the MEN1 tumour suppressor gene.
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PMID:Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene. 809 2

Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.
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PMID:Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. 859 33

Carcinoid tumours may develop from enterochromaffin cells in the gastrointestinal tract. Benign insulin-producing tumours may develop from islet cells, whereas other islet cell tumours might derive from multipotent stem cells in the pancreatic ducts. The idea that multiple endocrine neoplasia type 1 (MEN-1) tumours in the pancreas originate from multipotent stem cells is supported by our demonstration that CD44 is expressed in exocrine cells, in gastrin-producing endocrine cells only and in some non-functioning islet cell tumours; there are no gastrin-producing cells in the adult pancreas. We have identified phospholipase C beta 3 (PLC beta 3) as the gene implicated in MEN-1. It appears to be a tumour suppressor gene since it is expressed in endocrine pancreatic tumours, some lung carcinoids, and medullary thyroid carcinomas. So neuroendocrine tumours might have a dual growth-regulating system, involving both traditional growth factors through the tyrosine kinase system and also G-protein-mediated growth signals. Deletion of PLC beta 3, which is an important enzyme in the signal transduction pathway of G-protein-mediated signals, might be important in the growth regulation of neuroendocrine tumours. It is proposed that its deletion causes dysregulation of growth control in neuroendocrine cells, with possible distortion of the apoptotic process. In the last stage of the disease, tumour biology is altered and becomes more aggressive. Further, chromogranin A may be both a tumour marker for neuroendocrine tumours and a growth-promoting agent for neuroendocrine tumour cells; it is a very good marker of tumour mass but is also related to poor prognosis of survival. Mutation analyses of PLC beta 3 and studies of the growth-promoting effect of chromogranin are ongoing and should lead to more effective therapies.
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PMID:Biological aspects of neuroendocrine gastro-enteropancreatic tumours. 881 67


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