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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor-suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.
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PMID:Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. 760 4

Chromosome band 9p21 is deleted frequently in non-small cell lung carcinoma (NSCLC), and the p15 and p16 cyclin-dependent kinase-4 inhibitor genes map within this deletion region. Recent studies demonstrated deletion of p15 and p16 in NSCLC metastases and cell lines, suggesting a role for these genes in NSCLC progression. We now report p15 and p16 copy number, as determined by fluorescence in situ hybridization with a P1 contig, in 18 primary NSCLCs. Codeletion of p15 and p16 was found in 15 of 18 NSCLCs, and 1 of the 3 tumors with normal p15 and p16 copy number had a nonsense mutation in exon 2 of p16. We conclude that p15 and p16 are deleted and/or mutated in most primary NSCLCs. Two observations, however, support the involvement of at least one additional tumor suppressor gene on chromosome 9. These observations are: (a) the large size (> 100 kb) of most NSCLC p15/p16 deletions; and (b) the absence of exon 2 mutations in most retained NSCLC p15 and p16 alleles.
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PMID:Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. 760 11

The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.
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PMID:Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. 762 55

Four cyclin-dependent kinase inhibitors called p15, p16, p21 and p27 have been identified in mammals. Because these proteins participate in the control of cell cycle, they are potential targets for somatic mutations during carcinogenesis. In order to document the prevalence of p15 and p16 alterations in gliomas, we looked for loss of heterozygosity of chromosome 9p where these genes are localized. Allelic losses were observed in 31 of 44 investigated cases. In all cases they involved the p15/p16 locus. We then looked for mutations in the p16 and p15 genes in 46 gliomas. A total of three DNA variants were observed which were all present in the matched constitutional DNA. They may be unrelated to tumor development. A single somatic mutation was detected. It involved a C to G substitution in codon 93 of p16 and is predicted to change a threonine into an arginine. Taken together, these data indicate that inactivation by point mutation of these two cyclin-dependent kinase inhibitors is uncommon in glial tumor carcinogenesis, but that there may be a tumor suppressor gene on 9p in the vicinity of p16 and p15 genes.
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PMID:Frequent loss of heterozygosity on chromosome 9, and low incidence of mutations of cyclin-dependent kinase inhibitors p15 (MTS2) and p16 (MTS1) genes in gliomas. 763 Jun 44

The tumor suppressor genes p16INK4A and p15INK4B map to the 9p21 chromosomal locus and are either homozygously deleted or mutated in a wide range of human cancer cell lines and tumors. Although chromosome 9 abnormalities have been described in non-Hodgkin's lymphomas (NHLs), to date, the mutational status of these genes has not been determined for these malignancies. A total of five cell lines and 75 NHLs were examined for homozygous deletions or point mutations in the coding regions of both the p15 and p16 genes using Southern blot and/or polymerase chain reaction-single-strand conformation polymorphism analyses. Homozygous deletions of either the p16 gene or both the p15 and p16 genes were observed in one diffuse large B-cell lymphoma cell line and two uncultured lymphomas consisting of one large B-cell and one mixed T-cell lymphoma. In contrast, point mutations were not detected in either the cell lines or lymphomas. These results indicate that the rate of alterations in the p15 and p16 genes is low for lymphomas, but loss of p16 and/or p15 may be involved in the development of some lymphomas.
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PMID:Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-Hodgkin's lymphomas. 763 61

The cyclin-dependent kinase 4-inhibitor (CDK41; p16; or MTS1) gene has been proposed as a candidate for a tumor-suppressor gene located in chromosome 9p21, a frequently deleted region in a wide spectrum of human cancers, including leukemias. Recent studies disclosed that it was frequently deleted or mutated in a variety of primary human cancers, including acute lymphoblastic leukemia. The purpose of this study is to figure out the precise manners and frequencies of p16 gene inactivation in diverse hematopoietic tumor types and thus to clarify its significance in development of human hematopoietic malignancies. A total of 410 tumor specimens from patients with primary hematopoietic malignancies were examined for deletions of the p16 gene as well as the neighboring p15 gene and the nearby interferon alpha gene by Southern blot analysis. Tumor-specific mutations or small deletions of the p16 gene were also studied in 74 patients using single-strand conformation polymorphism analysis and direct sequencing. Loss of the p16 gene was most frequently observed among the three genes examined and was found in 59 of the 410 patients: 2 of 134 with acute myelocytic leukemia, 41 of 105 with acute lymphocytic leukemia, 2 of 15 with chronic lymphocytic leukemia, 5 of 14 with adult T-cell leukemia, 4 of 33 with non-Hodgkin's lymphoma, 3 of 8 with mixed-lineage leukemia, and 2 of 61 with chronic myelocytic leukemia. In 16 of the 59 patients, the p16 deletions occurred due to rearrangements within the small region between the p15 exon 2 and the p16 exon 2. Tumor-specific mutations or small deletions of the p16 gene were not detected in the 74 patients examined, including 12 of 14 patients with hemizygous deletions of the gene. Loss of the p16 gene is frequent in and highly specific to lymphoid malignancies (54 of 183 [30%] in lymphoid tumor v2 of 219 [1%] in myeloid tumors; P < .0001). The deletion analyses strongly suggest that the p16 gene is a tumor-suppressor gene located in chromosome 9p21 that is involved in development of human lymphoid tumors. Gene deletions but not minute mutations should be the predominant mechanism of p16 gene inactivation in these types of tumors.
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PMID:Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies. 763 63

The CDKN2 gene on chromosome 9p21 encodes the p16 inhibitor of cyclin D/cyclin-dependent kinase 4 complexes. Mutations and deletions of CDKN2 have been frequently identified in cell lines, whereas most primary tumors have demonstrated a lower frequency of alteration. To assess the role of CDKN2 in endometrial tumorigenesis, 34 tumor samples were examined for loss of heterozygosity at 9p21 and mutation in CDKN2. To identify tumors that had lost 9p21, samples were genotyped with markers flanking the CDKN2 locus. The frequency of CDKN2 mutation in endometrial carcinomas was determined by single-strand conformation variant analysis and direct sequencing of variants. Of the 34 tumors examined, three revealed loss of 9p21 sequences. Two samples were characterized by point mutations in CDKN2, one of which also showed loss of 9p21 sequences.
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PMID:Low frequency of CDKN2 mutation in endometrial carcinomas. 764 59

Deregulated expression of cyclin D1 occurs in several types of human cancer. Since it often results from a specific chromosomal abnormality, this over-expression is likely to be significant in the development of the disease. Cyclin D1 is also implicated in virally induced tumors in mice and transgenic models based on ectopic expression if cyclin D1 recapitulate features of the naturally occurring tumors. By these criteria, as well as its effects in transfected rodent cells, cyclin D1 has the hallmarks of a cellular proto-oncogene. Although the normal role of cyclin D1 is not well understood, its oncogenic properties appear to involve functional interactions with cyclin-dependent kinases, the retinoblastoma gene product and the MTS1/p16 tumor suppressor gene.
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PMID:Cyclin D1 as a cellular proto-oncogene. 764 9

We have analyzed 12 microsatellite markers on chromosome 9p in 54 paired cutaneous malignant melanoma (CMM) tumors and normal tissues. Forty-six percent of the tumors, including two in situ CMMs, showed loss of heterozygosity (LOH) at 9p. Only one tumor was homozygously deleted for 9p markers. The smallest deleted region was defined by five tumors and included markers D9S126 to D9S259. Loss of eight or more markers correlated significantly with worse prognosis (P < .002). Among the primary tumors, 87.5% of those with large deletions have a high risk of metastasis, as compared with only 18% of those without deletions or with loss of fewer than 8 markers (P < .001). It was not possible to demonstrate homozygous deletions of p16 in any of the CMM tumors. In four tumors, the LOH for 9p markers did not involve p16. The reported data suggest the existence of several tumor suppressor genes at 9p that are involved in the predisposition to and/or progression of CMM and exclude p16 from involvement in the early development of some melanoma tumors.
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PMID:Chromosome 9p deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 (CDKN2) gene. 766 66

The CDKN2 gene located on chromosome 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16. This gene is a putative tumor-suppressor gene because of its frequent alterations in many kinds of tumor cell lines. We analyzed the CDKN2 gene to evaluate its alterations in 52 primary specimens of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) of B-cell origin by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. By Southern blot analysis, we showed homozygous deletion of the CDKN2 gene in 3 of 42 patients with B-NHL (7.1%). After screening by PCR-SSCP analysis, direct sequencing identified one missense mutation at codon 72 (nucleotide 233) and two frameshifts due to a 35-bp deletion arising at codon 49 (nucleotides 163 to 175) in patients with B-NHL (3 of 42, 7.1%). In the patient carrying the missense mutation, hemizygous deletion of the CDKN2 gene was also suspected. In this study, we detected alterations in CDKN2 in 6 of 42 patients (14.3%) with B-NHL and in none of 10 patients with B-CLL. Our results suggest that the CDKN2 alterations contribute in tumorigenesis in some patients with B-NHL.
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PMID:Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas. 767 Jan 11


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