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)

Inherited mutations in the CDKN2A/INK4a/MTS1 tumour suppressor gene on chromosome 9p21 are associated with familial predisposition to melanoma and other tumour types. Nonsense and missense mutations are also found in a variety of sporadic cancers, and over 140 sequence variants have already been recorded in the literature. In assessing the relevance of these variants and for counselling members of affected families, it is important to distinguish inactivating mutations from harmless polymorphisms. Existing functional assays have frequently reached conflicting conclusions and no single test appears adequate. Here we evaluate a number of alternatives including a novel assay based on retroviral delivery of p16INK4a cDNAs into human diploid fibroblasts. Among the 17 sequence variants analysed, three distinct categories can be distinguished: those that abrogate the binding of p16INK4a to CDK4 and CDK6, those that alter the properties of the protein without preventing it from interacting with CDKs, and those that have no discernible effect on protein function. These distinctions can be rationalized by considering the impact of the amino acid changes on the three-dimensional structure of the protein.
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PMID:Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information. 1049 96

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
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PMID:Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. 1080 23

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.
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PMID:Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families. 1095 21

Approximately 10% of human cutaneous melanoma cases occur in families with the familial atypical multiple mole melanoma (FAMMM) syndrome, which is characterised by the familial occurrence of melanomas and atypical precursor naevi. A melanoma-associated gene has been mapped to 9p2l, encoding for the tumour suppressor gene CDKN2A. Worldwide, germline mutations in melanoma kindreds implicate this cell cycle regulator (p16) as a susceptibility gene for malignant melanoma. Most FAMMM families registered at the Leiden Pigmented Lesions Clinic share the same CDKN2A inactivating deletion (P16-Leiden). Presymptomatic DNA diagnosis will now be available for P16-Leiden positive FAMMM family members at the Leiden University Medical Centre.
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PMID:[From gene to disease; from p16 to melanoma]. 1110 70

The chromosome 9p21 region has been described to be frequently deleted in several neoplasias. The cyclin dependent kinase inhibitor 2A (CDKN2A or P16) gene was cloned in this region and identified as a tumour suppressor gene. However, much evidence indicates the existence of another tumour suppressor gene located proximal to the CDKN2A gene, which could be involved in cutaneous malignant melanoma (CMM) initiation. In the present report we have further investigated this 9p21 chromosomal region and cloned and characterised a novel gene within it (C9orf11). This gene shares no similarities to any known gene or predicted protein representing a novel human gene. Nevertheless, a putative leucine zipper pattern is located at the C-terminal end of the predicted protein, suggesting that it could dimerise. C9orf11 encodes for a protein of 294 amino acids with a predicted molecular mass of 32.8 kDa. C9orf11 is organised in eight exons that encompass a region of approx. 13 kb. Expression analysis demonstrates that C9orf11 is highly expressed in testis, although minor expression was seen in other tissues. Mutations in the C9orf11 gene were not detected in CMM families that were negative for CDKN2A mutations. Two SNPs for the C9orf11 gene have been identified, which could be used in segregation or association studies for other disorders.
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PMID:Isolation and characterisation of a novel human gene (C9orf11) on chromosome 9p21, a region frequently deleted in human cancer. 1111 25

The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumours, commonly astrocytoma. Germline deletions of the region on 9p21 containing the CDKN2A and CDKN2B genes and CDKN2A exon 1beta have been reported in kindreds, implicating contiguous tumour suppressor gene deletion as a cause of this syndrome. We describe a family characterized by multiple melanoma and neural cell tumours segregating with a germline deletion of the p14(ARF)-specific exon 1beta of the CDKN2A gene. This deletion does not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. Our results are consistent with either: (i) loss of p14(ARF) function being the critical abnormality associated with this syndrome, rather than contiguous loss of both the CDKN2A and CDKN2B genes as suggested previously; or (ii) disruption of expression of p16 by mechanisms as yet unknown.
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PMID:A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. 1113 14

The molecular events involved in pancreatic cancer are becoming increasingly well characterized, with mutations in the dominant oncogene KRAS and the tumour suppressor genes TP53, CDKN2A and MADH4 being typically observed. However, other genetic abnormalities remain to be identified and molecular cytogenetics may be useful to detect chromosomal loci involved in recurrent rearrangements. We have used spectral karyotyping to characterize cytogenetic aberrations in a panel of 20 human pancreatic carcinoma cell lines and confirmed their identities by dual and triple color fluorescence in situ hybridization. The most common partial or whole-arm gains involved 5p, 7q, 12p, 1q, 7p, 5q, 9p, 9q and 11p. The most common partial or whole-arm losses affected 9p, 11q, 18q, 3p, 2q and 1p, as well as the short arms of the acrocentric chromosomes. Spectral karyotyping allowed us to identify a number of recurrent structural aberrations, all of them unbalanced: most frequently i(5)(p10), del(11)(q23), i(12)(p10), i(1)(q10), del(7)(q22) and del(10)(p11). Spectral karyotyping mapped the complex aberrations occurring in pancreatic cancer cell lines and identified non-random patterns of chromosomal rearrangement. This comprehensive characterization should be useful to direct future investigation. The observation that loss at 11q and gains at 5p with i(5)(p10) and 12p with i(12)(p10) are more frequent changes than previously reported would justify more intensive investigation of these chromosomal regions.
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PMID:Non-random chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping. 1116 59

Nineteen specimens from primary human malignant mesotheliomas obtained from 19 patients were screened for activating point mutations in the oncogenes N-ras and CDK4 by combined RFLP-PCR/SSCP analysis. In addition, all tumours were screened for deletions and point mutations in the tumour suppressor genes p53, p16INK4a (CDKN2A) and p14ARF (exon-1beta) by combined multiplex-PCR/SSCP analysis. No mutations were found in N-ras, p53 and CDK4. Three tumours displayed homozygous deletion (co-deletion of exons 1, 2 and 3) of p16INK4a. One of them displayed additional homozygous deletion of p14ARF (exon-1beta). Two silent point mutations and 2 polymorphisms were found in p16INK4a in 3 tumours. Our preliminary data indicate that disarrangement of the Rb1 pathway may be involved in mesothelioma formation.
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PMID:Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas. 1117 13

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.
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PMID:INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. 1170 35

There is increasing evidence that predisposition to some cancers has a genetic component. There is a high incidence of loss of heterozygosity on chromosome 9, in the region of tumour suppressor gene, CDKN2A (also known as p16), in sporadic squamous cell cancer of the head and neck (SCCHN). To investigate the possibility that CDKN2A may be involved in the inherited susceptibility to SCCHN, the 3 coding exons of CDKN2A were sequenced in 40 patients who had developed a second primary cancer after an index squamous cell cancer of the head and neck. No mutations were found and we conclude that CDKN2A mutations do not play a major role in cancer susceptibility in this group.
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PMID:No germline mutations in CDKN2A (p16) in patients with squamous cell cancer of the head and neck and second primary tumours. 1172 Apr 78


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