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

Homozygous and hemizygous deletions of 9p21 are the earliest and most common genetic alteration in bladder cancer. The identification of two cell cycle regulators, CDKN2 and CDKN2B, that map to the common region of deletion has prompted the hypothesis that they are critical tumor suppressor genes in this malignancy. However, controversy as to whether these genes are the only or even the most important target in bladder cancer oncogenesis remains. To more clearly determine the effect of these 9p21 alterations, we mapped the homozygous deletions and performed a detailed mutational and expression analysis for CDKN2, CDKN2B and a closely linked gene, methylthioadenoside phosphorylase (MTAP), in 16 established bladder cancer cell lines. Nine of the 16 lines exhibit large (30 to > 2000 kb) homozygous deletions on 9p21. All deletions include at least one exon of CDKN2, eight of nine include CDKN2B, and six of nine include MTAP. MTAP function correlates with the genomic deletions. SSCP and sequence analysis does not reveal any inactivating point mutations of CDKN2 or of CDKN2B in any of the cell lines without homozygous deletions, and all express the CDKN2 and the CDKN2B mRNA as well as the encoded p16 protein. The p16 protein levels vary widely and are correlated with absent pRb expression. We conclude that the 9p21 deletions in bladder cancer usually inactivate the CDKN2. CDKN2B, and MTAP genes but that CDKN2 is the most common target. Other mechanisms for inactivating this gene in bladder cancer appear to be uncommon.
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PMID:The 9p21 region in bladder cancer cell lines: large homozygous deletion inactivate the CDKN2, CDKN2B and MTAP genes. 887 83

Genetic studies of chromosome arm 9p have indicated the presence of one or more tumor suppressor genes involved in genetic susceptibility to various types of human cancers. To define the extent of the specific deletion of 9p21-22 in human breast cancer, we have analyzed loss of heterozygosity and homozygous deletion of 9p21-22 in 68 paired blood and tumor samples by using fluorescent multiplex polymerase chain reaction (PCR). Of these tumors, 43% (29/68), including two ductal carcinomas in situ (DCIS), showed allele loss at one or more loci analyzed. Homozygous deletion for 9p markers was detected in 7/68 (10%) of tumor samples. Eleven tumors showed allele loss at all informative loci, and 18 tumors showed selective deletion on 9p21-22. Allele deletions in six tumors did not involve microsatellite markers flanking CDKN2. The smallest common region of deletion could be defined between D9S171 and D9S126. No significant associations were observed between deletion of 9p21-22 and any of the histopathological parameters analyzed. However, the abundance of deletions of this chromosomal region still suggests that loss and inactivation of putative tumor suppressor gene(s) located on 9p21-22 may be involved in the pathogenesis of breast cancer.
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PMID:Frequent allele loss on 9p21-22 defines a smallest common region in the vicinity of the CDKN2 gene in sporadic breast cancer. 888 2

An understanding of the biological significance of the multiple genetic alterations identified in clinical bladder cancers to the stepwise pathogenesis of the disease is evolving. Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease. p53 and pRb alterations are also known to occur in early stage bladder carcinoma in situ where they are thought to represent a poor prognosis for tumor progression. Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain. Amplification and/or overexpression of the oncogenes epidermal growth factor receptor and erbB2 are associated with later stage disease. Finally, recent findings generated using in vitro transformation systems with human uroepithelial cells provide strong evidence that loss of genes on 3p, which occurs in approximately 20% of bladder cancers, and/or gain of genes on 20q play an important role in blocking HUC cellular senescence. This latter phenotype should represent a critical step in oncogenesis, as cells that do not senesce can survive to accumulate the multiple genetic alterations associated with invasive and metastatic bladder cancers. Further understanding of the biochemical mechanisms underlying these genetic changes will provide the additional information needed to design better strategies for bladder cancer intervention and treatment.
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PMID:A molecular genetic model of human bladder cancer pathogenesis. 889 68

The genetic basis of spontaneous melanoma formation in spotted dorsal (Sd) Xiphophorus platyfish-swordtail hybrids has been studied for decades, and is adequately explained by a two-gene inheritance model involving a sex-linked oncogene, Xmrk, and an autosomal tumor suppressor, DIFF. The Xmrk oncogene encodes a receptor tyrosine kinase related to EGFR; the nature of the DIFF tumor suppressor gene is unknown. We analyzed the gentic basis of UV-B-induced melanoma formation in closely related, spotted side platyfish-swordtail hybrids, which carry a different sex-linked pigment pattern locus, Sp. We UV-irradiated spotted side Xiphophorus platyfish-swordtail backcross hybrids to induce melanomas at frequencies 6-fold higher than occur spontaneously in unirradiated control animals. To identify genetic determinants of melanoma susceptibility in this UV-inducible Xiphophorus model, we genotyped individual animals from control and UV-irradiated experimental regimes using allozyme and DNA restriction fragment length polymorphisms and tested for joint segregation of genetic markers with pigmentation phenotype and UV-induced melanoma formation. Joint segregation results show linkage of a CDKN2-like DNA polymorphism with UV-B-induced melanoma formation in these hybrids. The CDKN2-like polymorphism maps to Xiphophorus linkage group V and exhibits recombination fractions with ES1 and MDH2 allozyme markers consistent with previous localization of the DIFF tumor suppressor locus. Our results indicate that the CDKN2-like sequence we have cloned and mapped is a candidate for the DIFF tumor suppressor gene.
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PMID:A CDKN2-like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish-swordtail hybrids. 891 41

The p16INK4a was isolated as a gene which binds and inhibits the cyclin-dependent kinase 4. Other laboratories reported that the isolated gene frequently homozygously deleted within chromosome 9p21 was the p16INK4a. The p16INK4a gene was thought be a hot gene like the p53 gene at the time. Nevertheless, the gene was thought to be a false tumor suppressor gene due to the low incidence the alterations of the gene in various surgical tumor samples. Since then, there have been a lot of reports supporting that p16INK4a is a really tumor suppressor gene including the reports on the high incidence of p16INK4a alterations in some kinds of tumors, on the higher incidence of p16INK4a alterations in the metastatic tumors than that of the primary tumors, on the G1 arrest of p16INK4a lack cells transfected with p16INK4a cDNA, and on the inactivation of p16INK4a gene by hypermethylation. Therefore, the p16INK4a gene has become the tumor suppressor gene, lately. Moreover, the INK4 family including p15INK4b, p18INK4c, and p19INK4d was isolated. These reports taken together, p16INK4a and INK4 family might play important roles in the genesis and development of cancer.
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PMID:[Molecullar structure and function of the p16/INK4a/CDKN2/MTS1 and the INK4 family, and their association with carcinogenesis]. 892 Jun 70

Various molecular genetic abnormalities have been reported in esophageal carcinoma. These include amplification of the chromosome 11q13 region containing cyclin D1, EXP1 and EMS1 genes, and the oncogenes, the epidermal growth factor receptor gene, EGFR/c-ERBB1, and c-myc. Loss of heterozygosity (LOH) at several chromosome loci and point mutation of the p53 and p16/CDKN2 tumor suppressor genes have also been described. Mutations of p53 gene and LOH at 3p and 9q loci were investigated in esophageal epithelial dysplasia. In contrast, amplification of cyclin D1, EGFR, c-myc and other genes was accumulated in advanced tumors with invasion. Cyclin D1 amplification is found more in metastatic lesions than in primary tumors.
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PMID:[Genetic events during development of esophageal squamous cell carcinoma]. 892 Jun 74

The culture of hepatocytes isolated from C3H mouse liver results in the spontaneous development of colonies of liver epithelial cells that possess some features of the hepatocytes. These liver epithelial cells frequently have a loss of chromosome 4, and become neoplasms which are hepatocellular carcinomas by transfection with the activated c-Ha-ras gene. The suppression of malignant phenotypes by mouse chromosome 4 has already been shown by fusion between normal and malignant mouse cells. We established a total of six liver epithelial cell lines from C3H mice in order to investigate the presence of a tumor suppressor gene(s) on chromosome 4 in mouse hepatocarcinogenesis, and performed an allelotype analysis in seven microsatellites on chromosome 4 by the comparative multiplex PCR method. The result of analysis revealed that three of the six liver epithelial cells had allelic imbalances in four microsatellite loci, especially, two liver epithelial cell lines showed homozygous deletion in the D4MIT77 locus. Then, we investigated the status of the mouse homolog of p16/CDKN2 gene (mouse p16) on chromosome 4 by the comparative multiplex PCR method, and detected the homozygous deletion in two liver epithelial cell lines. Our result thus supports the theory that alterations of tumor suppressor gene(s) located on chromosome 4 may play a role in mouse hepatocarcinogenesis. Mouse p16, which is an inhibitor of cyclin dependent kinase 4, may suppress the cancer development in mouse hepatocarcinogenesis, or suppress liver cell immortalization.
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PMID:Homozygous deletion of mouse homolog of p16/CDKN2 gene on chromosome 4 in mouse liver epithelial cells in culture. 892 97

Inhibitors of cyclin-dependent kinases provide a major mechanism of negative regulation on cell cycle progression. Defects in the function of the CDK inhibitors may lead to uncontrolled cell proliferation and potentially facilitate tumorigenesis. The p16INK4 family of CDK inhibitors specifically prevent the phosphorylation of the retinoblastoma susceptibility gene product, pRb, by inhibiting the kinase activity of CDK4 and CDK6, thereby keeping pRb in its active form as a growth suppressor. The loss of p16INK4 inhibitory activity would, therefore, have the same consequence as the loss of pRb growth suppressing activity. The p16INK4 family currently includes four members, p15INK4b, pl6INK4a, pl8INK4c and p19INK4d. Two members, p15INK4b and pl6INK4a have been found to be deleted and mutated in a variety of human tumor-derived cell lines and primary tumors. In the present study we have examined the genomic status of the newly isolated p19INK4d gene in 75 tumor-derived cell lines; 13 immortalized, transformed or normal cell lines; 19 ovarian tumors and 18 acute myelogenous leukemias. No deletions or point mutations were observed in the pl9INK4d gene. A genetic polymorphism at codon 30 (CGC-->CGG) in exon 1 of the pl9INK4d gene was observed in 10% of the samples under investigation. In the same set of samples, p16INK4a was found to be homozygously deleted in 32% of the tumor derived cell lines. These results together with our previous data that showed a 22% deletion frequency in p15INK4b and rare alterations in the pl8INK4c gene, indicating that the p16INK4a and pl5INK4b, but not the p18INK4c and pl9INK4d genes, are frequently mutated in human tumors. Hence, members of the p16INK4 CDK inhibitor family, while evolutionary related and biochemically indistinguishable, carry out distinct biological functions.
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PMID:Lack of mutation in the cyclin-dependent kinase inhibitor, p19INK4d, in tumor-derived cell lines and primary tumors. 893 52

Cyclin-dependent kinase-4 inhibitor genes (INK4) regulate the cell cycle and are candidate tumor-suppressor genes. To determine if alterations in the coding regions of the p18 and p19 genes, which are novel members of the INK4 family and if they correlate with the development of human cancer, 100 human cancer cell lines were analyzed. Two other INK4 gene family members, p15INK4b/MTS2 and p16INK4/MTS1 genes were also analyzed. Homozygous deletions of the p15INK4b/MTS2 gene were detected in 29 cancer cell lines. Thirty-five homozygous deletions and 7 intragenic mutations of the pl6INK4/MTS1 gene were also detected in these cell lines. Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19. In p16INK4/MTS1 expression analysis, 5 cell lines with both authentic and alternative spliced p16INK4/MTS1 mRNA had no detectable p16INK4/MTS1 protein. These results suggest the hypotheses that either post-translational modification or enhanced degradation may be responsible for the lack of detection of the p16INK4/MTS1 protein. Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression. All of these cell lines expressed the p18 or p19 protein, with the exception of SKOV3, which did not express p19. Therefore, the INK4 gene family may be divided into 2 groups. One group includes p15INK4b/MTS2 and p16INK4/MTS1, in which genetic and epigenetic alterations might contribute to the development of human cancers. The other group includes p18 and p19, in which somatic mutations are uncommon in many types of human cancer, and their role in human carcinogenesis and cancer progression is uncertain.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. 893 42

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.
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PMID:Cancer cell cycles. 893 49


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