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)

The inhibitor of cyclin-dependent kinase 4, CDKN2 (also known as p16INK4 or MTS-1, multiple tumor suppressor gene 1), has been mapped to 9p21. The gene has been shown to be deleted or mutated in high frequency in human melanoma cell lines and familial melanoma patients, suggesting that it could be a melanoma suppressor gene. How these observations are related to tumorigenicity and metastasis of human melanoma is not clear however. To test the role of CDKN2 in human melanoma metastasis, 14 human melanoma cell lines with different metastatic abilities in nude mice were analysed for possible abnormalities in the CDKN2 gene. Homozygous deletions that resulted in a lack of gene expression were found in six of 14 cell lines tested. SSCP-direct sequencing revealed point mutations in three other cell lines. One cell line displayed CC to TT transitions which constitute a hallmark of ultraviolet-induced DNA damage. Overall, abnormalities in the CDKN2 gene were found in nine of 14 (64%) cell lines tested. Homozygous deletion and lack of gene expression were found in several low tumorigenic and nonmetastatic melanoma lines, whereas other metastatic cells did not exhibit abnormalities in the CDKN2 gene. These data suggest that the absence of normal CDKN2 does not confer growth advantage to melanoma cells in vivo and that the production of metastasis by human melanoma cells can occur in the absence of CDKN2 gene abnormalities.
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PMID:Abnormalities in the CDKN2 (p16INK4/MTS-1) gene in human melanoma cells: relevance to tumor growth and metastasis. 747 63

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.
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PMID:Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. 747 13

Deletion of 9p21-22 is a common genetic alteration in dysplastic, in situ, and invasive head and neck squamous cell carcinoma (HNSCC). However, a candidate tumor suppressor gene (TSG) at this site has thus far not been identified in HNSCC. We report homozygous deletion of the recently identified multiple tumor suppressor I (MTSI)/cyclin-dependent kinase-4-inhibitor (CDKN2) gene mapped to 9p21, which encodes the p16 protein, a regulator of cyclin-dependent kinase 4, in six of 16 HNSCC cell lines. We also show absence of the CDKN2 mRNA in all cell lines with CDKN2 deletion as well as in an additional two cell lines without deletion. Overall, we have identified 9p abnormalities in 12 of 16 (75%) cell lines, at least nine of which involved CDKN2. We further demonstrate that the CDKN2 deletion in HNSCC is located within a previously described region of allelic loss between D9S171 and IFNW, which spans a 4 cM region of 9p. However, examination of 36 primary tumors revealed genetic alterations in only seven of 36 (19%) tumors. These results suggest that genetic alterations at CDKN2 are frequent in HNSCC cell lines, but the role of this gene in primary tumors is less compelling. CDKN2 does not appear to be the only TSG on 9p21 in HNSCC, and our results suggest that another region of deletion exists proximal to the IFNW locus.
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PMID:Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. 754 12

UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumor cells was not elucidated. Here we show that UV-B can induce interleukin 8 (IL-8) mRNA and protein secretion in human cutaneous melanoma with negligible expression of IL-8. UV-B-induced IL-8 was constitutively expressed 60 days after irradiation in tumors implanted in mice. Induction of IL-8 was UV-B dose dependent and blocked by cyclohexamide, indicating that de novo protein synthesis is required for its expression. The UV-irradiated cells demonstrated enhanced tumorigenicity and metastatic potential in nude mice. The increase in tumorigenicity and metastatic ability could be explained by the increase in Mr 72,000 type IV collagenase activity and angiogenesis attributed to the induction of IL-8 after irradiation. The acquisition of the metastatic phenotype induced by UV-B could not be attributed to abnormalities in the p53 or MTS-1 (p16INK4) genes. To the best of our knowledge, this is the first report to show that UV-B can increase the aggressiveness of human cutaneous melanoma for growth and metastasis.
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PMID:Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. 754 20

Deletions of chromosomal band 9p21 have been detected in various tumor types as well as in more than 20% of acute lymphoblastic leukemia (ALL). These deletions frequently include the entire interferon (IFN) gene cluster as well as the methylthioadenosine phosphorylase (MTAP) gene. Recently, the CDKN2 gene (p16INK4A, MTS I, CDK41) was proposed as a candidate tumor-suppressor gene on 9p21 because it is frequently deleted in cell lines derived from multiple tumor types. To determine if CDKN2 or another closely related gene on 9p is the target of 9p deletions in ALL and other hematologic malignancies, we analyzed 20 primary patient samples (13 ALL, 2 acute myeloid leukemias [AML], and 5 non-Hodgkin's lymphomas [NHL]) with 9p rearrangements using Southern blot analysis, fluorescence in situ hybridization (FISH), and single-strand conformation polymorphism (SSCP) for alterations of CDKN2. Homozygous deletions of the CDKN2/CDKN2B (p15) region were detected in 10 cases (50%; 6 ALL, 2 AML, and 2 NHL). In 1 additional case, the intensity of the Southern blot band was significantly reduced, suggesting a CDKN2 deletion in a subpopulation of the malignant cells. No CDKN2 or CDKN2B rearrangements were seen. The IFN gene cluster was homozygously deleted in 2 of 15 (13%) analyzed cases, whereas the MTAP gene was deleted in 6 of 15 cases (40%). In addition, hemizygous deletions of the CDKN2 region were identified in 6 ALL cases using interphase FISH. No point mutation of the coding region of CDKN2 was detected by SSCP in these cases. We conclude that CDKN2 is the most frequently homozygously deleted marker on 9p. The absence of point mutations in the coding region of CDKN2 in cases with hemizygous 9p deletions and the frequent codeletion of MTAP, CDKN2B, and other yet unidentified neighboring genes suggest that the simultaneous deletion of these genes may be necessary for the selective growth advantage of malignant cells.
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PMID:Refined mapping of genomic rearrangements involving the short arm of chromosome 9 in acute lymphoblastic leukemias and other hematologic malignancies. 754 47

The bombesin-like peptides can function as autocrine growth factors in lung cancer and candidate tumor suppressor genes on chromosomes 3 and 9 play important roles in lung cancer. Bombesin-like peptides can function as mitogens for normal bronchial epithelial cells and lung cancer cell lines. The monoclonal antibody directed against gastrin releasing peptide and bombesin, 2A11, can inhibit the growth of small cell lung cancer in vitro and in vivo and intravenous administration has induced a clinical remission in a patient with relapsed small cell lung cancer. The loss of a portion of one of the two short arms of chromosome 3 (3p) is identified in nearly 100% of tumor cell lines and tumors from patients with small cell lung cancer. Introduction of chromosome 3 into tumor cell lines suppresses their tumorigenicity in athymic nude mice, one of the characteristics of the cancer phenotype. Both copies of the candidate tumor suppressor gene on chromosome 9, CDKN2, are deleted in approximately one-fourth of lung cancer cell lines examined and the protein product of CDKN2, p16 is undetectable in one-third of the lung cancer cell lines studied. The CDKN2 gene is inactivated more commonly in non-small cell lung cancer than small cell lung cancer while the retinoblastoma gene is inactivated more commonly in small cell lung cancer than non-small cell lung cancer. It appears that a single defect in this cell cycle pathway is necessary for unregulated growth in lung cancer and current evidence suggests these defects differ between small cell and non-small cell lung cancer.
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PMID:Biology of small cell lung cancer. 755 56

The tumor suppressor gene CDKN2/p16/MTS1, located on chromosome 9p21, is frequently inactivated in many human cancers through homozygous deletion. Recently, we have reported another pathway of inactivation that involves loss of transcription associated with de novo methylation of a 5' CpG island of CDKN2/p16 in lung cancers, gliomas, and head and neck squamous cell carcinomas. We now show that this aberrant CpG island methylation also occurs frequently in cell lines of breast cancer (33%), prostate cancer (60%), renal cancer (23%), and colon cancer (92%) and is associated with loss of transcription. Primary tumors of the breast (31%) and colon (40%) also displayed de novo methylation of this CpG island. This alteration of p16 in colon cancer was particularly striking, since inactivation does not occur through homozygous deletion in this tumor type. Our data show that in tumors, de novo methylation of the 5' CpG island is a frequent mode of inactivation of CDKN2/p16 and also firmly demonstrate that CDKN2/p16 is one of the most frequently altered genes in human neoplasia.
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PMID:Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. 755 21

Loss of heterozygosity on 9p21, where the p16/CDKN2 tumor suppressor and the p15INK4B cell cycle regulator genes are located, is a common genetic alteration in bladder cancer. However, it has been difficult to demonstrate homozygous deletions and intragenic mutations in either of these two genes in primary transitional cell carcinomas (TCC) of the bladder. Similarly, colon cancer-derived cell lines have shown no homozygous deletions of the p16/CDKN2 locus in contrast to a wide variety of tumor-derived cell lines. We have investigated abnormal methylation of the 5' CpG islands of the p16/CDKN2 and p15INK4B genes as an alternative mechanism of inactivation of these genes in bladder and colon cancers. De novo methylation of the 5' CpG island of p16/CDKN2 was observed in 12 of 18 (67%) uncultured bladder TCCs and in 2 of 3 (67%) bladder cell lines. In contrast, only 1 of 10 (10%) colon carcinomas showed methylation of the 5' CpG island of p16/CDKN2. It was striking to find that this region was extensively methylated and the gene not expressed in the normal colonic mucosa of 6 of 10 (60%) patients with colon cancer, whereas 5 of the corresponding colon tumors showed no methylation and high levels of p16/CDKN2 expression. Our data show a significant correlation (P = 0.00001, two-sided) between the absence of p16/CDKN2 expression and methylation of its 5' CpG island in bladder tumors, cell lines, and normal colon mucosa. In contrast, no association was observed between expression and methylation status of the 5' CpG island of p15INK4B. Our results suggest that the p16/CDKN2 tumor suppressor gene may be inactivated by methylation of its 5' CpG island in TCCs of the bladder. We also present evidence of methylation of the 5' CpG island in this autosomal gene in normal colonic tissue.
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PMID:Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. 755 22

To study mutation of the CDKN2 gene in prostate cancer, samples from 51 Japanese patients and four human prostate cancer cell lines were examined by single-strand conformation polymorphism analysis and direct sequencing. Only one out of 51 (2%) patients revealed a mutation, which was a 24 bp deletion from the 5'-untranslated region to codon 3, resulting in loss of the initiation site. One of the four cell lines revealed a missense mutation, a GAC-->TAC (Asp-->Tyr) at codon 84. These results indicate that mutation of the CDKN2 gene is rare in prostate cancer and thus does not contribute significantly to the pathogenesis of human prostate cancer. Prostate cancer cell lines may acquire more frequent abnormality of the CDKN2 gene than tumor tissues.
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PMID:Mutational analysis of CDKN2 (CDK4I/MTS1) gene in tissues and cell lines of human prostate cancer. 755 77

The tumor suppressor candidate p16INK4 is a cyclin-dependent kinase inhibitor that inhibits cell proliferation. The p16 coding gene is often mutated in glioblastomas, pancreatic adenocarcinomas and melanoma-prone pedigrees, but, until recently, the significance of these allelic variants has remained unclear. Here, we used interaction mating and coprecipitation to measure interaction of seven p16 allelic variants detected in melanoma-prone pedigrees with Cyclin-dependent kinases (Cdks). We found that most variants were deficient in interaction with Cdk4 and Cdk6. One defective variant was found both in cancer prone families and in the control population and therefore previously defined as a common polymorphism. Another variant, which is weakly linked to familial cancer, is only slightly affected in interaction with Cdks. These results are consistent with the idea that p16 allelic variants that decrease Cdk interaction predispose individuals who carry them to an increased risk of cancer. Moreover, they suggest that determination of affinity between p16 mutants and partner proteins may help identify functionally-significant allelic variants not detected by classical human genetic techniques.
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PMID:p16 proteins from melanoma-prone families are deficient in binding to Cdk4. 756 78


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