Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of nonsmall cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations were observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or II disease [two of seven (29%)] and stage III or IV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.
 ...
PMID:Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. 747 13

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.
 ...
PMID:Replacement of the p16/CDKN2 gene suppresses human glioma cell growth. 788 35

The cyclin-dependent kinase inhibitor known as p16 (CDK41, CDKN2, INK4A, MTS1) has been proposed as a tumor suppressor gene on chromosome segment 9p21. We have evaluated CDKN2 alterations in 34 non-small cell lung cancers (NSCLCs) with matched normal tissue controls and in 9 NSCLC cell lines by Southern blotting, single-strand conformation polymorphism (SSCP) with the polymerase chain reaction, and direct sequencing. In addition, loss of heterozygosity at chromosome segment 9p21, with the use of the microsatellite marker D9S171, was studied in these samples. Whereas CDKN2 was either deleted or mutated in NSCLC cell lines at a high frequency (6/9, 67%), alterations were much less frequent (7/34, 21%) in primary tumor samples. Only one sample contained a point mutation in exon 1 of CDKN2. In addition, two samples had homozygous deletions of CDKN2 in exon 1; one had a homozygous and three a hemizygous deletion of exon 2. Possibly normal tissue contaminating our tumor samples may have masked homozygous deletions in these cases. Four patient samples had LOH in the region of CDKN2 on chromosome segment 9p21; two of these samples had potentially inactivating alterations of CDKN2; one sample had a mutation of CDKN2, and the other had a homozygous deletion of exon 1. In summary, inactivation of CDKN2 is implicated in the development of about 20% of NSCLC, but the possibility of another tumor suppressor gene on chromosome segment 9p21 important in lung cancer cannot be eliminated.
 ...
PMID:Alterations of CDKN2 (p16) in non-small cell lung cancer. 858 32

The product of the p16/CDKN2 locus, p16ink4, negatively regulates the cell cycle through binding and inactivation of cyclin-dependent kinases (CDKs) 4 and 6. This locus is frequently targeted for deletion in cell lines and primary tumor tissues. In gliomas, although up to 50% do not have detectable expression of p16/CDKN2 protein or mRNA, often the gene is wild type in sequence. Here, we tested the hypothesis that transcriptional repression of p16/CDKN2 in gliomas may be mediated by aberrant methylation of the CpG island, which is in the 5' region of the locus. Partial rather than complete p16/CDKN2 methylation was detected in 24% (10 of 42) of the gliomas, regardless of tumor grade, but was not observed in normal brain (0 of 10). We tested whether this partial methylation could inhibit expression in a human tumor cell line in which suppressed p16/CDKN2 expression was associated with both methylation and tightly compacted chromatin around the p16/CDKN2 promoter. Exposure of these cells to 5-aza-2-deoxycytidine resulted in a dramatic increase in promoter accessibility and induction of p16/CDKN2 expression, indicating that chromatin structure, CpG island methylation, and p16/CDKN2 expression are intimately associated. Taken together, these data suggest that methylation occurs in only a subset of cells within gliomas and that the methylation-associated inactivation of p16/CDKN2 expression observed in many common human cancers may mechanistically result from structural changes in the chromatin containing the p16/CDKN2 locus.
 ...
PMID:Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. 862 19

Cancer has been proposed to develop by a process of stepwise accumulation of growth-advantageous genetic alterations which result in the evolution of clones which are outgrowths of such rare cells [1]. This model has recently been extensively tested in human gliomas, the most common primary tumor of the adult central nervous system. Temporal disease progression involves an interplay between growth-suppressing and growth-promoting genes. Specifically for gliomas, genetic studies have indicated loss of germline heterozygosity for chromosome 17p; mutation of the p53 gene; overexpression of the platelet-derived growth factor-alpha receptor; allelic losses of chromosomes 22q, 13q, and 19q; deletion of the interferon-alpha and beta and CDKN2 loci on chromosome 9p; amplification and rearrangement of the epidermal growth factor receptor gene, and monosomy of chromosome 10. The following discussion details these genetic alterations and their consequences for the biology of glioma progression with the ultimate aim of providing new avenues for clinical intervention.
 ...
PMID:Molecular biology of malignant degeneration of astrocytoma. 881 14

To define the involvement of p16/CDKN2 and p15/MTS2 inactivation in ovarian tumorigenesis and the association of these inactivation events with histological types and clinical stages of ovarian tumors, we analyzed homozygous deletion and somatic mutation of p16/CDKN2 and p15/MTS2 genes, as well as hypermethylation of the 5'-CpG island of the p16/CDKN2 gene, in 49 primary ovarian tumors and 6 ovarian carcinoma cell lines. We found homozygous deletions of p16/CDKN2 and p15/MTS2 in 6 (12%) and 5 (10%) primary tumors, respectively. Somatic mutation of p16/CDKN2 was found in only 1 primary tumor, but mutation of p15/MTS2 was not detected in any sample. None of the 28 primary tumors or 6 cell lines was hypermethylated at the 5'-CpG island of p16/CDKN2. The incidence of inactivation of p16/CDKN2 in primary tumors was significantly higher in the advanced stages (7 of 29) than in the early stages (0 of 14). Seven of 9 alterations in p16/CDKN2 and p15/MTS2 were observed in serous (3 of 12), endometrioid (3 of 9) and clear-cell (1 of 4) carcinomas. However, only normal sequences of these genes were detected in mucinous carcinomas. Loss of heterozygosity (LOH) at the IFNA locus was detected in 1 of 19 (5%) tumors, but no change at the D9S171 locus was observed in 17 tumors. These results suggest that: (i) homozygous deletion is the main mechanism of inactivation of p16/CDKN2 and p15/MTS2 in ovarian tumorigenesis; (ii) inactivation of p16/CDKN2 and p15/MTS2 may be the histological type-specific events involved in ovarian tumorigenesis; and (iii) inactivation of p16/CDKN2 is potentially involved in the progression of ovarian tumors in advanced stages.
 ...
PMID:Inactivation of p16/CDKN2 and p15/MTS2 genes in different histological types and clinical stages of primary ovarian tumors. 898 Feb 48

CDKN2 (p16(INK4A)/MTS1) is found to be mutated in a variety of human tumor types. To explore the involvement of CDKN2 in prostate carcinogenesis, alterations of CDKN2 were examined in 116 human prostate tissues and cell lines and xenografts. Markedly reduced expression of CDKN2 mRNA was found in 43% (26 of 60) of untreated primary carcinomas, whereas no alteration was observed in 10 benign prostatic hyperplasias. In 17 matched sets from individual patients, 41% of cancerous tissues in contrast to 6% of noncancerous tissues expressed low levels of CDKN2 mRNA, supporting the role of CDKN2 as a tumor suppressor in prostate cancer. Alteration of CDKN2 was observed in each prostate tumor cell line, including one with a missense mutation, and in one of three xenograft tumor tissues derived from primary carcinomas. Two cell lines (PC-3 and TSU-Pr1) expressed only CDKN2 E1beta transcripts, indicating that the expression of CDKN2 E1alpha and E1beta are under separate control in the prostate. A high level of CDKN2 expression was related to abnormal RB1 in one primary tumor and in the DU145 cell line, which expressed the mutated CDKN2 allele. Analysis of genomic DNA indicated that altered CDKN2 expression in primary carcinomas of the prostate was more frequently due to down-regulation of transcription (five of seven) than deletion of the gene (two of seven). Additionally, CDKN2 mRNA was induced in nonexpressor cell lines by treatment with 5-aza-2'-deoxycytidine. This study demonstrates that alteration of CDKN2 is one of the most frequent genetic abnormalities in prostate cancer and may contribute to prostate carcinogenesis.
 ...
PMID:Frequent alteration of CDKN2 (p16(INK4A)/MTS1) expression in human primary prostate carcinomas. 981 78

Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the cyclin D1 gene and deficient expression of the retinoblastoma gene in 42 and 28% of these tumors, respectively. The immunohistochemical analysis showed that these RT-PCR results are correlated with a significant increase in the number of positive cells for cyclin D1 and a moderate decrease in the expression of Rb protein, respectively. The analysis of cyclin D1, Rb, p15(INK4b) and p16(INK4a) showed that 75% of lymphomas had alterations in these genes and indicates that the Rb pathway is frequently altered in mouse primary T cell lymphomas. Moreover, 31% of lymphomas presented simultaneous alterations in at least two of these genes, suggesting the importance of concurrent alteration of different Rb pathway regulators. In addition, we have characterized these samples for mutational status of the N-ras and K-ras genes. We have only detected mutations in codon 12 of K-ras in six of 49 lymphomas (12%). Interestingly, five of these lymphomas also showed alterations in at least one of the Rb pathway regulators analyzed here. Taken together, these data suggest that deregulation of the Rb pathway regulators and/or oncogenic activation of K-ras may represent a common important clue in progression of murine T cell lymphomas.
 ...
PMID:Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas. 1046 10

Glioblastoma multiforme (GBM) is the most common primary tumor occurring in the central nervous system of adults. Although progress has been made in clinical management of this tumor, little is known about the molecular defects underlying the initiation and progression of GBM. To address these issues, we have characterized five cases of GBM using cytogenetics, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and direct sequencing. All of these tumors were observed to have clonal chromosome aberrations. Complicated chromosome translocations including der(18)t(2;4;12;18), der(X)t(X;10)(q27.1;p12.1) and der(10)t(10;15)(p11.23;q11.2), and der(1) (:1p31-->1q44::7q11. 3-->7qter) were seen in three tumors. Loss of the CDKN2 gene was noted in four tumors. A gain of copy number of the Cathepsin L gene was seen in two tumors. Amplification of the CDK4, MDM2, and GLI/CHOP genes was noted in two tumors, and amplification of the PDGFR gene was detected in one tumor. Mutation of exon 5 of the TP53 gene was found in three tumors. No mutation of the BCL10 gene was detected in five cases of GBM analyzed, although deletion of chromosome 1p was seen in two tumors. These results provide information for further investigation of GBM.
 ...
PMID:Molecular and cytogenetic analysis of glioblastoma multiforme. 1110 17

Loss of heterozygosity of several specific genomic regions is frequently observed in neuroblastoma tumors and cell lines, but homozygous deletion (HD) is rare, and no neuroblastoma tumor suppressor gene (TSG) has yet been identified. We performed a systematic search for HD, indicative of a disrupted TSG, in a panel of 46 neuroblastoma cell lines. An initial search focused on a well-characterized consensus region of hemizygous deletion at 1p36.3, which occurs in 35% of primary neuroblastomas. Each cell line was screened with 162 1p36 markers, for a resolution of 13 kb within the consensus 1p36.3 deletion region and 350 kb throughout the remainder of 1p36. No HDs were detected. This approach was expanded to survey 21 known TSGs, specifically targeting intragenic regions frequently inactivated in other malignancies. HD was detected only at the CDKN2A (p16INK4a/p14ARF) gene at 9p21 and was observed in 4 of 46 cell lines. The observed region of HD included all exons of both CDKN2A and the closely linked CDKN2B (p15INK4b) gene for cell lines LA-N-6 and CHLA-174, all exons of CDKN2A but none of CDKN2B for CHLA-179, and only 104 bp within CDKN2A exon 2 for CHLA-101. All four deletions are predicted to inactivate the coding regions of both p16INK4a and p14ARF. HD was observed in corresponding primary tumor samples for CHLA-101 and CHLA-174 but was not present in constitutional samples. These results suggest that for neuroblastoma, large HDs do not occur within 1p36, most known TSGs are not homozygously deleted, and biallelic inactivation of CDKN2A may contribute to tumorigenicity in a subset of cases.
 ...
PMID:Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. 1121 68


1 2 3 Next >>