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

We examined 24 human bladder cancer tissues for possible mutations in the entire coding region of the human DNA polymerase beta gene using polymerase chain reaction analysis, single-strand conformational polymorphism analysis of RNA, and sequence analysis. DNA polymerase beta gene mutations were observed in four of the 24 cases (16.7%) and included three missense point mutations and a single base insertion. The single base insertion was also observed in our previous study of human prostate cancer, suggesting that this region may be a hot spot for mutation of the DNA polymerase beta gene. No clinical or pathological association was found among the four cases that contained the mutation. Three of the four cases with DNA polymerase beta gene mutation had mutations of the p16 or RB genes or loss of heterozygosity of the p53 and APC gene loci. The results of the study presented here suggest that DNA polymerase beta gene mutations, in combination with mutations of tumor suppressor genes, may be involved in certain cases of human bladder cancer.
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PMID:DNA polymerase beta gene mutations in human bladder cancer. 856 64

We examined the frequency of cyclin-dependent kinase (CDK) N2 alterations in differentiated and anaplastic thyroid cancers to assess the involvement of CDKN2 in the development of these cancers. The CDKN2 gene, which encodes the cell-cycle regulator p16, was recently shown to be mutated or deleted in many tumor cell lines. Its role in the genesis of primary tumors is uncertain, however. Tumor and corresponding normal DNAs were prepared by microdissection of paraffin-embedded tissue blocks or from frozen surgical specimens of 15 papillary, 15 follicular, and five anaplastic thyroid carcinomas. The entire CDKN2 coding region was screened by single-strand conformational variant analysis and direct sequencing of variants. The presence of homozygous deletions was evaluated by multiplex polymerase chain reaction (PCR) analysis. Loss of heterozygosity (LOH) in the CDKN2 region was assessed by using flanking polymorphic markers. Two somatic missense mutations were found among the 35 thyroid cancers, one in a follicular tumor and one in an anaplastic tumor. Multiplex PCR suggested the presence of homozygous deletion in one anaplastic tumor and hemizygous deletions in four tumors. LOH studies revealed loss of 9p sequences in four follicular (27%) and two anaplastic (50%) cancers. Our data suggest that alterations in CDKN2 played a role in a minority of thyroid cancers (three of 35). LOH in the region of CDKN2 is seen in a significant proportion of follicular and anaplastic but not papillary cancers. Loss of 9p sequences suggests a role for a tumor suppressor gene in the development of follicular and anaplastic thyroid cancers.
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PMID:Infrequent CDKN2 mutation in human differentiated thyroid cancers. 856 66

Homozygous deletions of the tumor suppressor gene p16/MTS1 were reported in a wide variety of tumors and tumor cell lines. Its product inhibits the phosphorylation of the retinoblastoma protein (pRb) by CDK4 and CDK6. Because phosphorylation of pRb is a major regulatory event in the activation of the transcription factor E2F, a role for p16 in the regulation of E2F-dependent transcription was presumed. We investigated the effect of the loss of p16 on E2F-mediated transcription in a tumor progression model consisting of three cell lines originating from a common precursor cell--one p16-positive cell line established from the primary biopsy and two lines derived from more advanced stages of the tumor representing the same cell clone after loss of p16. We observed up- and deregulation of E2F-dependent transcription during the cell cycle of the p16-negative cell clones, which returned to normal after transient expression of p16. This p16-dependent regulation affects a set of enzymes necessary for the activation of all four DNA precursors; it is paralleled by the interconversion of transcriptionally active free E2F and transcriptionally inactive higher molecular complexes of E2F and is dependent on the existence of endogenous pRb. Furthermore, we show that p16-negative cell clones exhibit a growth advantage compared to their p16-positive counterparts. One might speculate that one feature of tumor progression could be deregulation of E2F-dependent transcription caused by loss of p16.
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PMID:Loss of the p16/MTS1 tumor suppressor gene causes E2F-mediated deregulation of essential enzymes of the DNA precursor metabolism. 856 96

The growth suppressing activity of the retinoblastoma suspectibility gene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose kinase activity is negatively regulated by CDK inhibitors of the p16 family. We have examined the genomic status of two recently isolated p16-related CDK inhibitors, p15 and p18, in 15 normal and 73 tumor-derived cell lines established from 23 different tissues, as well as 26 invasive primary breast cancers and 20 acute myelogenous leukemias. p15 was found to be homozygously deleted in 22% of the tumor derived cell lines, but no point mutations were found in either the cultured cells or the two types of primary tumors. With the exception of one breast cancer cell line, no deletions or mutations were found in the p18 gene in either cultured cell lines or primary tumors. These results indicate that mutation of the p18 gene occurs rarely in human tumors. Thus, while they share a very similar biochemical mechanism of inhibiting the kinase activity of CDK4 and CDK6, members of the p16 gene family play different roles in controlling cell proliferation and suppressing tumor growth.
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PMID:Mutational analysis of the p16 family cyclin-dependent kinase inhibitors p15INK4b and p18INK4c in tumor-derived cell lines and primary tumors. 857 Feb 24

Recent research has yielded a dramatic increase in the number of connections between oncogenesis and the proteins which regulate the cell cycle. Three classes of protein which inhibit the activity of cyclin-dependent kinases (CDKs) have emerged as potential targets for oncogenic inactivation. p16 and related proteins inhibit the cyclin/CDK complexes which regulate the transition from G1 to S phase; numerous studies have revealed that p16 is mutated in most tumor cell lines and in some types of primary tumor. p21/WAF1/Cip 1 and the related p27Kip protein inhibit a broader range of cyclin/CDK complexes than p16. Although the absence of p21/WAF1/Cip1 from cyclin/CDK complexes is correlated with cellular transformation, no mutations in this gene have been found in tumors or tumor-derived cell lines. A third class of genes which are potential targets for oncogenic inactivation are the kinases and phosphatases which regulate the activity of cyclin/CDK complexes by phosphorylation and dephosphorylation of the CDK proteins. Disruption of any of these genes would result in loss of normal regulation of cell growth.
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PMID:Inhibitors of cyclin-dependent kinase and cancer. 858 12

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.
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PMID:Alterations of CDKN2 (p16) in non-small cell lung cancer. 858 32

The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.
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PMID:Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. 858 35

Primary lung adenocarcinomas in non-smoking females are increasing in the USA and Japan. Environmental factors such as passive smoking, asbestos, domestic radon, and hormonal effects have been implicated, but the etiology is still uncertain. We therefore analyzed point mutations of p16 gene, a newly characterized tumor suppressor gene, and compared the results with alterations of p53 gene in 28 primary lung adenocarcinomas in non-smoking Japanese females. There were no cases with somatic point mutation of p16 gene, except for one case with two germline mutations (silent mutations). In contrast, six out of 16 informative cases showed loss of heterozygosity of p53 gene using a TP53 microsatellite marker and 19 out of 28 cases showed expression of oncoprotein using DO-7 immunohistochemistry. These findings suggest that p16 gene alteration is a rare event in primary lung adenocarcinomas in Japanese non-smoking females, compared with alterations of the p53 gene.
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PMID:p16/CDKN2 gene and p53 gene alterations in Japanese non-smoking female lung adenocarcinoma. 860 61

Cdk4-mediated phosphorylation of Rb protein is inhibited by p16, a product of a possible tumor suppressor gene. We examined the expression of p16 and Rb protein by means of immunohistochemistry in 61 non-small cell lung cancers and have demonstrated an inverse relationship between the expression of p16 and Rb protein: 28/30 specimens that did not stain for p16 stained for Rb and 21/31 p16-positive specimens did not stain for Rb. Only 1 of the p16-negative specimens had a mutation of exon 2 of the CDKN2 gene. Our results indirectly support the theory that p16 expression is negatively regulated by the functional Rb protein.
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PMID:Inversely correlated expression of p16 and Rb protein in non-small cell lung cancers: an immunohistochemical study. 862 Dec 24

Mutational analysis of the p16/CDKN2 gene was conducted by direct sequencing of the whole coding sequence (exons 1-3 and flanking splicing sites) in 21 esophageal squamous-cell carcinomas and 3 adenocarcinomas from a high-incidence area of Italy. Two inactivating mutations were found in exon 1 of the gene (both in squamous-cell carcinoma), whereas no mutations were detected in exon 2, where most of the sequence changes reported so far have been located, or in exon 3. Southern blot analysis of exon 2 in this set of samples and in a complementary set of 12 tumor samples from France did not show homozygous deletions or detectable gene rearrangements. Thus, p16/CDKN2 gene alterations do not appear to play a major role in the group of patients examined.
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PMID:Low frequency of p16/CDKN2 gene mutations in esophageal carcinomas. 862 Dec 47


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