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)

Homozygous deletions of the cyclin-dependent kinase 4 (CDK4) inhibitor gene CDKN2 (p16, MTS1) have been demonstrated to occur frequently in human cancer cell lines of different origin. However, in most primary tumours the frequencies of CDKN2 deletions are not well defined. We studied primary samples of 100 patients with lymphoid leukaemias [B-lineage acute lymphoblastic leukaemia (ALL), n = 23; T-ALL, n = 7; B-cell chronic lymphocytic (B-CLL) or prolymphocytic (B-PLL) leukaemia, n = 50; T-CLL/T-PLL, n = 20] using fluorescence in situ hybridization (FISH) with eight overlapping cosmid clones covering the region on chromosome band 9p21 containing CDKN2. We did not observe any CDKN2 deletions in the 70 patients with chronic lymphoid leukaemias of B- or T-cell origin. Of the 23 patients with B-lineage ALL, one (4%) exhibited a CDKN2 deletion: in this patient, two clones were detected, one exhibiting a hemizygous and the other a homozygous deletion. On chromosome banding analysis, four patients with B-lineage ALL had a 9p aberration, whereas all CDKN2 copies were retained. In contrast, six of the seven (86%) patients with T-ALL exhibited CDKN2 deletions (homozygous, n = 4; hemizygous, n = 2). We conclude that hemizygous or homozygous deletions of the CDKN2 gene occur at high frequency in T-ALL and at low frequency in B-lineage ALL, supporting the role of this gene as a tumour suppressor, especially in T-ALL. However, from our data there is no evidence that CDKN2 is involved in the pathogenesis of chronic lymphoid leukaemias of B- or T-cell origin.
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PMID:CDKN2 gene deletion is not found in chronic lymphoid leukaemias of B- and T-cell origin but is frequent in acute lymphoblastic leukaemia. 854 31

Research on the genetic basis of CLL is progressing at a rapid pace. The development of new techniques such as FISH, comparative genomic hybridisation (CGH) and a whole range of molecular methods is being applied to identify abnormalities in this relatively common B-cell leukaemia. The abnormalities may be of a different nature. There are some which are clearly associated with particular forms of the disease and usually with aggressive characteristics. The best examples are deletions at 11q23 seen in younger patients with generalised lymphadenopathy and inferior prognosis; trisomy 12, commonly associated with an increased proportion of prolymphocytes (CLL/PL) and more progressive disease; 17p abnormalities, chiefly mutations and deletions of p53, although rare, seem to be associated with transformation such as Richter syndrome, with CLL/PL and poor response to therapy. Abnormalities at 13q, though not correlated with particular clinical syndromes, are the subject of intense interest due to the possibility that one or more tumour suppressor genes relevant to the pathogenesis of CLL may be identified. Two areas in which work is being focused are 13q14 and 13q12. Finally, the incidence of familial cases of CLL, which has been known for a number of years, will lead to an international effort to collect familial cases, which ultimately will allow a genetic linkage study to discover a CLL "susceptibility gene". The presentations at the IWCLL were up-to-date, stimulating and pointed the way forward to further rapid progress in this exciting field.
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PMID:The search for genetic clues in chronic lymphocytic leukemia. 947 Oct 56

Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22-23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22-23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.
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PMID:Ataxia telangiectasia gene mutations in leukaemia and lymphoma. 1142 21

Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.
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PMID:Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia. 1209 50