Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sporadic and familial malignant melanoma susceptibility has been linked to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2) or p16 gene, has been shown to be deleted, mutated, or rearranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a M(r) 16,000 protein (p16) that plays a key role in cell cycle control by binding to the cyclin-dependent kinase 4 enzyme and inhibiting its ability to phosphorylate critical substrates necessary for transition past the G1 phase of the cell cycle. Thus, mutations or deletions of the CDKN2 gene could result in abnormal proliferation via defective cell cycle control. The correlation of 9p21 cytogenetic and molecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whether this gene is the CDKN2 gene. If so, then loss of p16 is potentially an initiating or early event in melanoma progression. To address the issues of what is the potential involvement of the CDKN2 gene in sporadic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2 occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our results suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in situ and the majority of primary invasive melanomas retain expression of this protein; and (b) potentially more related to invasiveness or the ability to metastasize, because 52% of primary invasive tumors and 72% of metastatic lesions show partial or complete loss of expression of p16.
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PMID:Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. 779 91

To define the extent of involvement of chromosome 9p in breast carcinogenesis, we performed microsatellite length polymorphism analysis of markers spanning this region. Of 24 primary breast carcinomas analyzed, we observed a high frequency (58%) of loss of heterozygosity or allelic imbalance affecting subregion 9p21-22. Mutational analysis of CDKN2 (p16) was performed to determine whether this gene was the target of such alterations. Of 21 tumors analyzed, only 1 showed a mutation of probable consequence, suggesting that CDKN2 appears not to be the target of loss of heterozygosity and indicating the possible existence of another tumor suppressor gene within this region. Additionally, since it has been suggested that some CDKN2 deletions and mutations could be due to an in vitro phenomenon, four immortal breast cell lines derived from normal epithelium, MCF10F, MCF12F, 184A1, and 184B5, were examined for loss or mutation of CDKN2. Two lines (MCF10F and MCF12F) showed homozygous deletions of CDKN2, and one (184A1) revealed a hemizygous deletion and a nonsense mutation in the remaining allele. This could imply an important role of CDKN2 in the control of immortalization or in vitro adaptation and is the first evidence of such in nontumor-derived cell lines. Additionally, this is the first report of frequent loss of heterozygosity in the 9p21-22 chromosome subregion of uncultured primary breast tumors.
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PMID:Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells. 779 17

To investigate the potential loss of tumor suppressor gene loci on chromosome 9 in human renal cell tumorigenesis we analyzed 42 paired normal and tumor DNAs with 18 polymorphic microsatellite markers spanning this chromosome. Fourteen of 42 (33%) tumors showed partial or complete deletion of chromosome 9. Deletion mapping provided evidence for the presence of a suppressor locus on both the short and long arm of chromosome 9. Homozygous deletion at 9p21-22 in one renal tumor and a selective deletion of distal 9q in another tumor localized the critical regions. The CDKN2/p16 gene was further investigated as a candidate suppressor locus on 9p21-22 by multiplex PCR, Southern analysis, and exon sequencing. We found no additional cases of homozygous deletion nor any rearrangements or point mutations of CDKN2/p16. This is the first report of 9p loss of heterozygosity, homozygous deletion of 9p21-22 and selective deletion of 9q in primary renal cell carcinomas. Understanding the molecular genetic basis of renal cell progression will require the isolation and characterization of additional tumor suppressor genes on chromosome 9.
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PMID:Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas. 781 48

Frequent homozygous deletions of the p16 (MTS1) gene encoding a cyclin-dependent kinase inhibitor were recently reported in various tumor cell lines including examples derived from lung cancers, but direct evidence for their occurrence in lung cancer patients has not been reported thus far. In the present study, alterations of p16 and/or p15, a p16-related cyclin-dependent kinase, were observed not only in lung cancer cell lines but also in the corresponding tumor specimens in vivo, excluding the possibility of in vitro artifacts. Interestingly, a clear specificity was also noted in terms of the affected histological subtype; i.e., only non-small cell lung cancers carried alterations (6 of 20 as compared to 0 of 20 small cell lung cancer cell lines).
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PMID:In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. 783 19

Nasopharyngeal carcinoma (NPC) is a malignancy which occurs at high incidence in southern China and southeast Asia. The molecular mechanism of this disease, however, is not well understood. Recently, a homozygous deletion and/or loss of heterozygosity on chromosome 9p21-22 was found in several primary NPCs (Huang et al., Cancer Res. 54: 4003-4006, 1994), suggesting that a potential tumor suppressor gene(s) residing in this region may play a role in nasopharyngeal carcinogenesis. Since p16/MTS1, a potential tumor suppressor gene, whose mutations/deletions are frequently found in variety of tumor cells, was mapped to chromosome 9p21, we investigated the possible involvement of this gene in the development of NPC by mutational and Northern blot analysis. SSCP-direct sequencing revealed no point mutations of the p16/MTS-1 gene in any of 42 primary NPC biopsies from three geographical regions nor in two NPC cell lines. We did, however, observe a codon 140ala-->thr polymorphism in the gene, which has been previously reported as a point mutation. Furthermore, Northern analysis revealed a decreased expression of the p16/MTS1 gene in two out of two NPC cell lines as compared with immortalized/nontransformed cell lines. These results suggest that down regulation rather than a point mutation of the p16/MTS1 gene may play a role in the genesis of NPC.
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PMID:No point mutation but decreased expression of the p16/MTS1 tumor suppressor gene in nasopharyngeal carcinomas. 786 58

The chromosome band 9p21-22 is frequently rearranged or deleted in a variety of tumors including hematological malignancies. This supports the notion of a tumor suppressor gene in this chromosome region. Indeed, the p16/MTS1 gene encoding a cyclin-dependent kinase (CDK) inhibitor has been shown to be frequently deleted and/or inactivated by nonsense mutations in a number of tumors. We have examined 98 DNA samples from blood, bone marrow cells and lymph node biopsies of patients with leukemia (ALL and AML) or lymphoma (follicular lymphoma and T-cell lymphoma), using Southern blot hybridization and a p16/MTS1-specific probe. Molecular abnormalities, mainly homozygous deletions, were found principally in ALL (8 out of 22 patients), much less frequently in AML (2/32) and lymphoma (2/32). While these data argue in favor of a large involvement of p16/MTS1 in ALL, AML and lymphomas appear to be less frequently implicated.
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PMID:Alterations of the putative tumor suppressor gene p16/MTS1 in human hematological malignancies. 788 34

The p16/CDKN2 gene has many features of a growth suppressor gene: it maps to 9p21, a frequent region of loss of heterozygozity in a variety of tumor types; it encodes an inhibitor of cyclin-dependent kinase 4; and its homozygous deletion is common in tumor-derived cell lines. However, the lower frequency of alteration of the gene in primary tumor tissue as compared to the cognate tumor cell lines has brought this interpretation into question. We have assessed the growth suppressive function of p16/CDKN2 by gene transfer. The introduction of full-length p16/CDKN2 cDNA caused marked growth suppression in p16/CDKN2-null human glioma cells, but was without significant effect in those cells with endogenous wild-type p16/CDKN2 alleles. These results provide functional evidence in support of the hypothesis that the p16/CDKN2 gene is a functional growth suppressor gene, at least in gliomas.
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PMID:Replacement of the p16/CDKN2 gene suppresses human glioma cell growth. 788 35

The multiple tumor suppressor 1 (MTS1) gene encoding the p16 inhibitor of cyclin-dependent kinase 4 is deleted or mutated in a wide variety of human tumor cell lines, but the importance of this gene as a tumor suppressor in vivo appears to be highly dependent on tumor type. Because MTS1/p16/CDKN2 and the homologous MTS2/p15 gene map to a region of chromosome 9p21, which is frequently deleted in malignant gliomas, we searched for lesions of these genes in primary biopsies of glioblastoma multiforme (GBM). Our analysis confirms a sizable frequency of homozygous deletion of MTS1/p16/CDKN2 (9/27 cases) and also reveals a low but detectable frequency of intragenic DNA lesions (one point mutation in exon 2 leading to premature termination) among GBMs that retain one or both copies of the gene. No mutations were found in exon 2 of MTS2/p15 (12 cases examined), and one GBM showed a DNA deletion breakpoint in the 30 kb between MTS1/p16/CDKN2 and MTS2/p15 resulting in deletion of MTS1/p16/CDKN2 with retention of MTS2/p15. In contrast to the high-grade tumors, none of 12 low-grade gliomas showed MTS1/p16/CDKN2 deletions. These data support a role for MTS1/p16/CDKN2 as a tumor suppressor gene in the in vivo evolution of GBMs. Given that two tumors with hemizygous MTS1/p16/CDKN2 deletions and loss of heterozygosity for chromosome 9p21 did not contain detectable intragenic mutations, there may be one or more additional relevant 9p21 tumor suppressor genes.
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PMID:MTS1/p16/CDKN2 lesions in primary glioblastoma multiforme. 788 43

Recently, it has been shown that the homozygous deletion of the cyclin-dependent kinase-4 inhibitor (CDK4I;p16) gene, which is mapped to chromosome 9p21, is frequently observed in a wide spectrum of human cancers, including leukemias. Therefore, the CDK4I gene is thought to be a putative tumor-suppressor gene. We report here that both alleles of the CDK4I gene were completely or partially deleted in human leukemia cells derived from both patients and established cell lines. Thirty-seven hematopoietic cell lines and samples from 72 patients with leukemias were examined for homozygous loss of the CDK4I gene locus by Southern blot analysis. We found that a part or the whole of the CDK4I gene was homozygously deleted in 14 of the 37 (38%) cell lines and 4 of 72 (6%) samples from leukemia patients, including 45 with acute myelocytic leukemia, 14 with acute lymphocytic leukemia (ALL), and 13 with chronic myelocytic leukemia in blastic crisis. In the cell lines, the homozygous deletion of the CDK4I gene was detected in a variety of cell lineages, whereas all 4 cases showing the homozygous deletion were confined to ALL. It should be noted that 2 of them had no cytogenetic abnormalities of chromosome 9. Our results suggest that loss of the CDK4I function may contribute to immortalization of human leukemia cells and play a causative role at least in development of human lymphocytic leukemias.
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PMID:Homozygous loss of the cyclin-dependent kinase 4-inhibitor (p16) gene in human leukemias. 791 62

The CDKN2 gene that encodes the cell cycle regulatory protein cyclin-dependent kinase-4 inhibitor (p16) has recently been mapped to chromosome 9p21. Frequent homozygous deletions of this gene have been documented in cell lines derived from different types of tumors, including breast tumors, suggesting that CDKN2 is a tumor suppressor gene involved in a wide variety of human cancers. To determine the frequency of CDKN2 mutations in breast carcinomas, we screened 37 primary tumors and 5 established breast tumor cell lines by single-strand conformation polymorphism analysis. In addition, Southern blot analysis was performed on a set of five primary breast carcinoma samples and five breast tumor cell lines. Two of the five tumor cell lines revealed a homozygous deletion of the CDKN2 gene, but no mutations were observed in any of the primary breast carcinomas. These results suggest that the mutation of the CDKN2 gene may not be a critical genetic change in the formation of primary breast carcinoma.
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PMID:Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. 792 51


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