Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated 34 oligodendroglial tumors (7 oligodendrogliomas, 11 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas) for deletion, mutation, hypermethylation, and expression of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes at 9p21. One anaplastic oligoastrocytoma carried a homozygous deletion including all 3 genes. None of the tumors demonstrated point mutations in any of the genes. Methylation-specific polymerase chain reaction (MSP) analysis and sequencing of bisulfite-modified DNA, however, revealed frequent hypermethylation of the 5'-CpG islands in CDKN2A, p14ARF, and CDKN2B. Partial or complete methylation of the majority of CpG sites analyzed from each gene was detected in 32% of the tumors at the CDKN2A gene and at a similar percentage (41%) of the tumors at the p14ARF gene and the CDKN2B gene. Most tumors with CDKN2A, p14ARF, and/or CDKN2B hypermethylation either lacked detectable transcripts from these genes or had lower mRNA levels than those determined for non-neoplastic brain tissue. There was a significant correlation between hypermethylation of these genes and the presence of allelic losses on chromosomal arms 1p and 19q. In addition, p14ARF hypermethylation was predominantly found in tumors without a demonstrated TP53 mutation. Taken together, our results indicate that hypermethylation of CDKN2A, p14ARF, and CDKN2B is an important epigenetic mechanism by which oligodendroglial tumors may escape from p53- and pRb-dependent growth control.
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PMID:Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes. 1176 89

We report on two children with cerebral gliomas showing extensive lipomatous change of tumor cells. One tumor was a large mass occupying the temporal and occipital lobes of the left hemisphere; the other was a cystic lesion with a mural nodule in the left frontal lobe. Histologically, both tumors were composed of glial cells that contained fat droplets coalescing into a single large droplet, thus resulting in an appearance similar to adipocytes. Immunohistochemistry showed GFAP positivity of tumor cells, which was maintained in the cytoplasmic rim of lipidized cells. Synaptophysin and neurofilaments were negative. Ki-67/Mib1 labeling index was low. Electron microscopy showed intracytoplasmic lipid vacuoles, abundant intermediate filaments and a basal lamina surrounding the cell bodies. Molecular genetic analysis of one tumor revealed no TP53 mutation (exons 4-10), no loss of CDKN2A, and no amplification of EGFR, CDK4 or MDM2. Both patients are alive and well after 3 and 7 years, respectively. However, one of them had to be re-operated on circumscribed local recurrences. Our cases represent a rare variant of low-grade astrocytoma that may be designated as "lipoastrocytoma".
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PMID:Lipoastrocytoma: a rare low-grade astrocytoma variant of pediatric age. 1181 Jan 81

The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription-polymerase chain reaction. The T-cell receptor (TCR)-gamma genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-beta, TCR-delta, TIA-1, granzyme B and perforin. Epstein-Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.
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PMID:A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion. 1184 84

Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2-10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60-80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), -Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11-14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12-21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, although abnormalities involving chromosome 17, e.g., i(17q), have repeatedly been shown to be ominous. However, the clinical impact of additional cytogenetic and molecular genetic aberrations is most likely modified by the treatment modalities used.
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PMID:Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. 1191 88

We determined inactivation of the CDKN2A (p16(INK4a) and p14(ARF)) gene in 21 cases of oesophageal squamous cell carcinoma (OSCC). The tumours were also analysed for mutations in exons 5-8 and allelic losses in the p53 gene. In addition, we screened the CDKN2B (p15 INK4b), CDKN2C (p18 INK4c), CDK4 and p53R2 genes for mutations in the tumour tissues. Besides concomitant alterations in the CDKN2A and p53 loci in more than half of the cases, our results showed that in 18 OSCC (86%) the CDKN2A (p16(INK4a) and p14(ARF) ) gene was affected through mutations, homozygous/hemizygous deletions and promoter hypermethylation. Eight out of 10 tumours with mutations or promoter hypermethylation specific to the CDKN2A/p16 INK4a gene showed loss of the wild-type allele. One tumour with a single base deletion in the N-terminus (codon 8) of the CDKN2A/p16(INK4a) gene carried a novel germ-line mutation or a rare polymorphism (Ile51Met) in exon 2 of the CDK4 gene. Promoter hypermethylation in the CDKN2A/p14 ARF gene was detected in 11 tumours. In the p53 gene 15 mutations were detected in 14 tumours. We detected an inverse relationship between CDKN2A/p16 INK4a inactivation and frequency of loss of heterozygosity at the p53 locus (OR 0.09, 95% CI 0.01-0.98; Fisher exact test, P-value approximately 0.03). Screening of nine exons of the p53R2 [Human Genome Organisation (HUGO) official name RRM2B] gene resulted in identification of a novel polymorphism in the 5' untranslated region, which was detected in four cases. Our results suggest that the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes involved in the two cell cycle pathways are major and independent targets of inactivation in OSCC.
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PMID:Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes are major targets for inactivation. 1196 Sep 18

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14(ARF). Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.
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PMID:INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. 1206 7

A case of intraductal oncocytic papillary neoplasm of the pancreas, with the rare progression to invasive carcinoma, is described. The intraductal oncocytic papillary neoplasm component had the features typical of this entity, with stratified layers of oncocytic cuboidal tumor cells growing in papillary and pseudopapillary arrangements within dilated pancreatic ducts. The invasive carcinoma formed a discrete fleshy tumor with well-circumscribed borders. The invasive carcinoma grew in solid lobules, subdivided by fine fibrovascular septae into predominantly organoid and trabecular growth patterns. Molecular analysis showed no loss of heterozygosity for microsatellite markers at the tumor suppressor loci of TP53, CDKN2A (p16/INK4A), and MADH4 (Smad4/DPC4) in the invasive carcinoma, although loss of heterozygosity was detected at one CDKN2A marker in the intraductal component. DNA sequencing of polymerase chain reaction amplification products of exons 1 and 2 of the CDKN2A gene showed no mutation in either tumor component. TP53 immunohistochemistry showed no increased levels of staining, consistent with the presence of wild-type gene product. Polymerase chain reaction and DNA sequencing showed no mutation of codons 12 and 13 of the KRAS proto-oncogene. These results suggest that intraductal oncocytic papillary neoplasm is a neoplasm with genetic changes that are distinct from typical pancreatic adenocarcinoma. The lack of mutation in these genes may be an explanation for the typically indolent clinical behavior of intraductal oncocytic papillary neoplasms.
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PMID:Genetic analysis of invasive carcinoma arising in intraductal oncocytic papillary neoplasm of the pancreas. 1217 96

Supratentorial primitive neuroectodermal tumours (sPNETs) are malignant central nervous system tumours of childhood which are histologically characterized by poorly differentiated neuroepithelial cells with the capacity for divergent differentiation into glial, neuronal, myogenic or melanotic lines. The histological differential diagnosis between sPNET and glioblastoma multiforme (GBM) may be difficult, particularly as GBMs can sometimes demonstrate a poorly differentiated PNET-like phenotype. To identify molecular genetic markers that may distinguish sPNET and GBM, we investigated 12 cerebral sPNETs and six GBMs from paediatric patients for genetic alterations of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 genes, as well as for allelic loss on chromosome arms 10q and 17p. Mutations of the TP53 tumour suppressor gene were found in one of 12 sPNETs (8%) and two of six GBMs (33%). None of the sPNETs but two of six GBMs (33%, including one GBM with a TP53 mutation) showed allelic losses on chromosome arm 17p. PTEN mutations were detected in one of 12 sPNET (8%) and one of six GBMs (17%). None of the sPNETs and GBMs carried a homozygous deletion involving the CDKN2A tumour suppressor gene. No amplification of the EGFR, CDK4 or MDM2 proto-oncogenes was detected. Taken together, our results indicate that paediatric GBMs differ from sPNETs by a higher incidence of allelic losses on 17p and TP53 mutations. In addition, the patterns of genetic alterations in sPNETs and paediatric GBMs appear to be distinct from those in cerebellar medulloblastomas and adult GBMs, respectively.
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PMID:Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. 1217 45

The CDKN2A locus on human chromosome 9p21 encodes two proteins, p16 and p14ARF, that mainly regulate cell cycle progression and cell survival via the pRb and p53 pathways, respectively. Germline mutations in CDKN2A have been linked to development of cutaneous melanoma in some families with hereditary melanoma. Due to overlapping open reading frames in exon 2, some mutations in this exon affect both p16 and p14ARF. We previously reported a 24bp deletion in CDKN2A exon 2 in a patient with multiple primary melanomas and melanoma heredity. To further clarify the possible role of the 24bp deletion for melanoma development, especially with respect to p14ARF, we have studied the cellular distribution and function of the resulting p14ARF del (77-84) and p16 del (62-69) mutant proteins. We found that p14ARF del (77-84) had decreased nucleolar localization, and was less efficient than wt p14ARF in stabilizing p53, inducing G1 cell cycle arrest, and inhibiting colony formation. The p16 del (62-69) mutant localized predominantly to the cytoplasm, did not induce G1 cell cycle arrest, and failed to suppress colony formation. We conclude that p14ARF del (77-84) has retained the ability to stabilize MDM2 and p53, but that it is less potent than wt p14ARF. This partial functional defect may complement the clearly defective p16 del (62-69) mutant and thus contribute to melanoma development in patients carrying the 24bp deletion in CDKN2A.
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PMID:A melanoma-predisposing germline CDKN2A mutation with functional significance for both p16 and p14ARF. 1217 54

During the initial indolent chronic phase of chronic myeloid leukemia (CML), the t(9;22)(q34;q11), resulting in the Philadelphia chromosome (Ph), is usually the sole cytogenetic anomaly, but as the disease progresses into the accelerated phase (AP), and eventually into aggressive blast crisis (BC), secondary aberrations, mainly unbalanced changes such as +8, i(17q), and +Ph, are frequent. To date, molecular genetic studies of CML BC have mainly focused on alterations of well-known tumor-suppressor genes (e.g., TP53, CDKN2A, and RB1) and oncogenes (e.g., RAS and MYC), whereas limited knowledge is available about the molecular genetic correlates of the unbalanced chromosomal abnormalities. Balanced secondary changes are rare in CML AP/BC, but it is not known whether cryptic chromosomal translocations, generating fusion genes, may be responsible for disease progression in a subgroup of CML. To address this issue, we used multicolor combined binary ratio fluorescence in situ hybridization (FISH), which allows the simultaneous visualization of all 24 chromosomes in different colors, verified by locus-specific FISH in a series of 33 CML cases. Two cryptic balanced translocations, t(7;17)(q32-34;q23) and t(7;17)(p15;q23), were found in two of the five cases showing the t(9;22) as the only cytogenetic change. Using several BAC clones, the breakpoints at 17q23 in both cases were mapped within a 350-kb region. In the case with the 7p15 breakpoint, a BAC clone containing the HOXA gene cluster displayed a split signal, suggesting a possible creation of a fusion gene involving a member of the HOXA family. Furthermore, one case with a partially cryptic t(9;11)(p21-22;q23) and an MLL rearrangement as well as a previously unreported t(3;10)(p22;p12-13) were identified. Altogether, a refined karyotypic description was achieved in 12 (36%) of the 33 investigated cases, illustrating the value of using multicolor FISH for identifying pathogenetically important aberrations in CML AP/BC.
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PMID:Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression. 1220 76


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