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)

Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
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PMID:The molecular biology of chronic myeloid leukaemia. 865 67

Molecular genetic analysis of breast cancers indicates that the mechanisms underlying tumorigenesis are complicated. Many oncogenes and tumour suppressor genes have been implicated, encoding proteins that are important at many levels of cell regulation, from cell surface molecules responding to external signals (eg ERBB2) to nuclear factors controlling gene transcription (eg TP53, MYC). Several correlations have been found between certain genetic events and clinical outcome and have therefore proved useful prognostic indicators. The mapping and cloning of genes important in familial breast cancers (eg BRCA1) have provided the essential tools for pinpointing the genes that may be critical in early stage breast cancer as well as for developing genetic tests for predicting carrier status in breast cancer families. Clarification of the molecular consequences of mutation in breast cancer associated genes is beginning to address the factors that drive a normal breast cell to change into a breast cancer cell. However, these studies are still in their infancy, and considerable research will be required to complete the picture.
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PMID:Molecular genetics of sporadic and familial breast cancer. 871 25

Comparative genomic hybridization was used to identify the regions of genomic gain and loss in the myeloid cell line HL-60. These included amplification at 8q24 corresponding to previous reports of overrepresentation of the MYC gene; loss of material from the short arms of chromosomes 9 (9p21-p23), 10, and 17; loss of the chromosome regions 9q32-qter and 14q11-q24; and an extra copy of chromosome 18. Additionally, deletion of the 5q11-q31 region was noted and was associated with translocation of chromosome 5 material to chromosomes 16 and a dic(5;17)(q11;p11) chromosome (previously described as mar 3). Loss of chromosome 5 material in myeloid malignancies, including the M2 subtype from which HL-60 was derived, is usually associated with interstitial deletions of the long arm, including the critical 5q31 region, resulting in a 5q- chromosome. The HL-60 cell line may be a useful model to investigate the role of potential tumour suppressor genes associated with loss of 5q material in myeloid leukaemias.
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PMID:Loss of the chromosomal region 5q11-q31 in the myeloid cell line HL-60: characterization by comparative genomic hybridization and fluorescence in situ hybridization. 872 84

BIN1 is a novel protein that interacts with the functionally critical Myc box regions at the N terminus of the MYC oncoprotein. BIN1 is structurally related to amphiphysin, a breast cancer-associated autoimmune antigen, and RVS167, a negative regulator of the yeast cell cycle, suggesting roles in malignancy and cell cycle control. Consistent with this likelihood, BIN1 inhibited malignant cell transformation by MYC. Although BIN1 is expressed in many normal cells, its levels were greatly reduced or undetectable in 14/27 carcinoma cell lines and 3/6 primary breast tumours. Deficits were functionally significant because ectopic expression of BIN1 inhibited the growth of tumour cells lacking endogenous message. We conclude that BIN1 is an MYC-interacting protein with features of a tumour suppressor.
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PMID:BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. 878 10

The polymerase chain reaction (PCR) offers a practical means of studying the molecular genetic features of lymphomas. The method is rapid and, as formalin-fixed, paraffin processed samples can be used, does not require special tissue handling procedures. PCR amplified immunoglobulin and T cell receptor gene rearrangements can be exploited as markers of clonality and lineage and genetic abnormalities such as chromosome translocations and mutations of oncogenes and tumour suppressor genes can be used to identify specific lymphoma types. Polymorphic X linked loci may also be used as markers of clonality in females. Direct sequencing of PCR amplified IGH variable regions has provided insights into the developmental stages, susceptibility to antigen drive and dissemination patterns of lymphomas. The role of oncogenes and tumour suppressor genes such as MYC and TP53 in lymphomas can be studied by PCR amplification of mutation hotspots and direct sequencing of products. Known viral and bacterial DNA can readily be identified using PCR and unknown organisms sought using conserved primers to amplify polymorphic sequences. PCR analysis of the lymphomas and related disorders has accelerated our understanding of their molecular biology and provides a practical tool with diagnostic and prognostic applications. Future development of in situ PCR methods will provide cellular localization of genetic defects and infectious agents.
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PMID:Polymerase chain reaction in the assessment of lymphomas. 954 84

Inactivation of tumour suppressor gene(s) (TSGs) on 3p appears to be a critical event in the pathogenesis of clear cell renal cell carcinoma (CC-RCC). Analysis of loss of heterozygosity (LOH) in sporadic RCC samples has implicated roles for TSGs in three specific regions of 3p in RCC development: (1) 3p12-p14, which includes the breakpoint of the familial t(3;8) constitutional translocation involved in hereditary RCC development and a recently cloned putative TSG, the FHIT gene: (2) 3p21.2-p21.3, a common region of deletion in many cancers including lung; and (3) 3p25-p26, which contains the von Hippel-Lindau (VHL) disease TSG. We and others have shown that most primary sporadic CC-RCCs contain somatic VHL gene mutations, clearly implicating inactivation of the VHL gene in the pathogenesis of CC-RCC. It is not known if CC-RCC without VHL gene mutations have alternative mechanisms of VHL gene inactivation or result from an alternative non-VHL pathway to RCC, e.g., inactivation of TSGs in 3p12-p21. We and others have reported hypermethylation and silencing of the VHL TSG in RCC from patients with VHL disease and in CC-RCC cell lines. However, the incidence and specificity of VHL methylation in primary sporadic RCC has not been defined. Therefore, we analysed methylation of the VHL, CDKN2, MYC, and H19 genes in primary RCC samples. Hypermethylation of the VHL promoter region was detected in 11% (11/99) of the primary RCCs analysed. In 10 of these tumours, there was no evidence of concomitant VHL gene mutation. VHL methylation was specific to CC-RCC (15%, 7/45) but was not detected in any non-CC tumours (n = 16). None of the 11 RCCs methylated at VHL had evidence of methylation at either CDKN2 or MYC (methylation at CDKN2 was, however, detected in 3%, or 1/33, of RCCs without VHL methylation). A normal methylation pattern at H19 was demonstrated in the three RCCs with methylated VHL analysed. Previous studies have suggested that, in addition to VHL, other 3p TSGs at 3p12-p14 and 3p21 may be involved in CC-RCC tumourigenesis. However, the interpretation of these studies has been difficult because information on VHL gene status has not been available for these data sets. Therefore, we investigated a subset of 55 sporadic RCCs (of known VHL gene methylation and mutation status) for LOH at polymorphic markers close to candidate TSG loci in the 3p14.2 and 3p21.2-p21.3 regions. Among tumours with LOH at one or more 3p markers, the incidence of 3p25 allele loss was higher in tumours with VHL alterations (mutation or methylation) than in those without. For tumours without detectable VHL alterations, the frequency of 3p14-p21 LOH was significantly higher than the frequency of 3p25-p26 LOH (93%, 13/14 vs. 43%, 6/14; P = 0.013), whereas, in RCC samples with VHL methylation or mutation, the frequency of 3p14-p21 LOH did not differ from that of sp25-p26 (72%, 18/25 vs. 59%, 13/22; P = 0.376). None of the 11 RCCs with 3p25 allele loss that were informative at 3p21 and 3p14 showed LOH at 3p25 only. These findings suggest that (1) VHL methylation is a specific and important event in the pathogenesis of CC-RCC; (2) in CC-RCC with 3p LOH but without VHL inactivation, mutations in TSGs at 3p14-p21 appear to have a primary role in tumourigenesis; and (3) inactivation of other 3p TSGs in addition to VHL may also be required for malignant transformation in tumours with VHL gene inactivation.
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PMID:Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. 962 31

A search was initiated towards the localization of novel mutated tumour suppressor genes that may be involved in adult leukaemia. For this purpose, we measured the occurrence of loss of heterozygosity (LOH) in nine patients with acute B-lineage leukaemia (ALL) and one with undifferentiated leukaemia (AUL). Eight leukaemias exhibited a diploid karyotype. For each patient, PCR products of 130 polymorphic microsatellite markers, located in subtelomeric areas of every autosomal chromosome arm were analysed to visualize LOH events resulting from reduplication of a single mutated chromosome or from mitotic recombination. These kinds of LOH events contribute most to LOH in model systems but cannot be detected by classical cytogenetic techniques. By comparing allelic PCR products in tumour cells with those in normal cells, LOH was found in tumour cells of one ALL patient at 9p which harbours the known p16INK4A tumour suppressor gene. In the AUL patient, however, LOH was detected at the telomeres of 4q and 21q, suggesting that these sites may contain novel tumour suppressor genes specifically involved in this form of leukaemia. In the DNA of tumour cells from eight out of 10 patients no LOH was detected. This is in contrast with the general assumption that LOH is a frequent phenomenon in ALL. However, some markers at telomeric regions of chromosomes were already homozygous in the control T-cells of several patients. For instance, we found in the DNA of control cells from one patient five consecutive microsatellites on 9p up to 9p43 which were homozygous and in three other patients homozygosity was observed in band 8q24, which includes the MYC gene. These observations indicate that LOH events already are present in non-cancerous putative stem cells and that mitotic recombination may be a very early event in leukaemogenesis.
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PMID:A search for novel tumour suppressor genes for adult acute leukaemia by allelotyping at sub-telomeric chromosomal regions. 968

In childhood acute lymphoblastic leukaemia (ALL) a number of genetic changes have been identified which provide diagnostic and prognostic information with a direct impact on patient management. The most significant abnormalities include the translocation, t(12;21)(p13;q22), giving rise to the ETV6/AML1 gene fusion; BCR/ABL arising from t(9;22)(q34;q11); re-arrangements of the MLL gene; the E2A/PBX1 from the t(1;19)(q23;p13); re-arrangements of MYC with the immunoglobulin genes and re-arrangements of the T cell receptor genes. Chromosomal deletions, particularly those of the short arms of chromosomes 9 and 12 and the long arm of chromosome 6, have been postulated to be the sites of tumour suppressor genes (TSG). Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (50-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL.
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PMID:The genetics of childhood acute lymphoblastic leukaemia. 1103 43

In acute lymphoblastic leukaemia (ALL) the karyotype provides important prognostic information which is beginning to have an impact on treatment. The most significant structural chromosomal changes include: the poor-risk abnormalities; t(9;22)(q34;q11), giving rise to the BCR/ABL fusion and rearrangements of the MLL gene; abnormalities previously designated as poor-risk; t(1;19)(q23;p13), producing the E2A/PBX1 and rearrangements of MYC with the immunoglobulin genes; and the probable good risk translocation t(12;21)(p13;q22), which results in the ETV6/AML1 fusion. These abnormalities occur most frequently in B-lineage leukaemias, while rearrangements of the T cell receptor genes are associated with T-lineage ALL. Abnormalities of the short arm of chromosome 9, in particular homozygous deletions involving the tumour suppressor gene (TSG) p16(INK4A), are associated with a poor outcome. Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (51-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL. Novel techniques in molecular cytogenetics are identifying new, cryptic abnormalities in small groups of patients which may lead to further improvements in future treatment protocols.
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PMID:Acute lymphoblastic leukaemia. 1164 Aug 71

The development of oral and head and neck squamous cell carcinomas occurs in relation with multiple events including mainly: loss of cycle cell control, evasion from apoptosis, telomerase reactivation. Complex interactions between a set of molecules, cell cycle proteins, tumour suppressor genes, oncogenes and the telomerase, occur in the multiple step process of carcinogenesis. The 2 main ways of control of the cell cycle rely on 2 tumour suppressor genes: the P53 gene and the retinoblastoma gene or RB gene. One of the regulation pathways or the 2 regulation pathways are disabled during the development of oral and head and neck squamous cell carcinomas. Most of the time, the inactivation of the P53 pathway results from a loss of function of the p53 protein, secondary to mutation and/or deletion of the P53 gene; It may also result of the amplification of the MDM2 gene and of the inactivation of the arf protein. The RB pathway leads to cell proliferation by loss of the p16 protein, by amplification of the cyclin D1 gene and less frequently by mutation of the RB gene or loss of the retinoblastoma protein. In India and South-East Asia, the activation of RAS and MYC oncogenes appears to be related with the presence of specific carcinogens in snuff and tobacco. By blocking apoptosis, the Bcl2 protein seems to increase the resistance of tumours to radiotherapy and chemotherapy.
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PMID:[Genic alterations in oral and head and neck squamous cell carcinomas: analysis of international literature]. 1278


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