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)

Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0-11. 1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1. 6-12.4), nevi on the feet (odds ratio 4.2; confidence interval 1. 4-12.5), total nevus number being at least 100 (nevi > or = 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0-11.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1. 1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1-3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma.
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PMID:Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. 1062 Jan 11

Although common among adult intracranial neoplasms, pediatric malignant astrocytomas (PMAs) comprise a relatively small proportion of the brain tumors that occur in children. The scarcity of such cases generally requires that molecular analyses of PMAs are based on the utilization of paraffin-embedded material, and here we have used 39 such specimens to examine the incidence and prognostic significance of oncogene and tumor suppressor gene alterations (including amplifications of EGFR, CDK4, and MDM2 as well as inactivating mutations of CDKN2A, TP53, and PTEN) in these tumors. In general, the frequency of alteration for the genes we have studied fell within ranges that have been reported for adult astrocytomas. However, EGFR amplification, which is usually observed in approximately 40% and 15% of adult grade 4 and grade 3 astrocytomas, respectively, was not detected in any member of this series. With regard to prognosis, PTEN mutations were significantly associated with decreased survival among grade 3 and grade 4 PMA patients, a potentially important observation because neither patient age nor tumor malignancy grade was correlated with outcome for these individuals. In total, our data suggest at least one significant distinction between the genetic etiology of pediatric and adult astrocytomas and additionally reveal that analysis of PTEN mutations in PMA patients may be useful in the differential diagnosis of these tumors.
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PMID:Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. 1063 44

A murine Ets2 target gene isolated by differential display cloning was identified as the phospholipase A2 activating protein (PLAA) gene. A 2.7-kb human cDNA demonstrating high homology to mouse and rat Plaa genes was then isolated and characterized. Human PLAA contains six WD-40 repeat motifs and three different protein kinase consensus domains. Fluorescence in situ hybridization (FISH) mapping placed PLAA on chromosome 9p21, a region frequently deleted in various cancers. A comprehensive mapping strategy was employed to define further the chromosomal localization of PLAA relative to CDKN2A within the 9p21 locus. Radiation hybrid mapping placed the gene 7.69 cR from WI-5735 (LOD >3.0), a marker in close proximity to CDKN2A and CDKN2B. Yeast artificial chromosome (YAC) mapping localized PLAA proximal to the CDKN2A/CDKN2B genes and to a region flanked by D9S171 and INFA commonly deleted in many neoplasms. Two YACs contained both PLAA and D9S259, a marker present in a second more proximal minimal deleted region observed in cutaneous melanoma and squamous cell lung carcinoma. Double-color fiber FISH mapping confirmed the location of PLAA centromeric to D9S171 and CDKN2A/CDKN2B. The mapping data suggest a possible tumor suppressor role for this gene.
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PMID:Chromosomal localization of phospholipase A2 activating protein, an Ets2 target gene, to 9p21. 1064 53

Gastric adenocarcinomas (n = 125) were analyzed by immunohistochemistry for the presence of p16, the CDKN2A gene product. This protein was lost in 31 of 125 cases (25%), and loss was associated with location of the tumor in the body of the stomach (P = .001). Loss of p16 was also associated with the presence of Epstein-Barr virus (EBV) in tumor cells as determined by in situ hybridization (P = .022). This effect may relate to anatomic site, because EBV-associated tumors originate more frequently in the body of the stomach. When p16 status was evaluated for ethnic origin of the patient (non-Hispanic white, Hispanic, or black), a strong trend (P = .057) was found for African-American patients to have fewer p16-negative tumors than other patients. This also may relate to anatomic location, because fewer tumors from black patients arose in the body of the stomach (P = .022). No significant associations were detected between p16 status and histological subtype (intestinal v diffuse), the presence of microsatellite instability, grade or stage of the tumor, or age, gender, or survival of the patient. In conclusion, p16 loss is quite common in gastric adenocarcinoma, and such loss is more common in EBV-infected tumors arising in the body of the stomach.
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PMID:Loss of p16/CDKN2A tumor suppressor protein in gastric adenocarcinoma is associated with Epstein-Barr virus and anatomic location in the body of the stomach. 1066 12

We examined 149 lung cancer cell lines for homozygous deletions using 24 DNA markers, which were mapped and ordered in chromosome band 9p21, to define the target regions for 9p21 deletions in human lung cancer. Homozygous deletions were detected in 39 (26%) cell lines and clustered at 2 independent regions. One was the region containing the p16/CDKN2A tumor suppressor gene, and this region was deleted in 32 (21%) cell lines. The other was the region containing D9S171, which is the locus approximately 3 Mb proximal to the CDKN2A locus. This region, designated as the D9S171 region, was deleted in 18 (12%) cell lines. Seven of the 18 cell lines had identical minimum deletions of a 17,036 bp sequence located 20 kb distal to the D9S171 locus. However, such a deletion was also observed in the corresponding B-lymphoblastoid cell line from 1 of the 7 cell lines and in 5 (16%) of 32 noncancerous tissues, suggesting that the deletion was a genetic polymorphism. By considering this polymorphism, 11 (7%) cell lines still had deletions at the D9S171 region. Two NSCLC cell lines showed deletions at the D9S171 region and retentions of the CDKN2A locus. Furthermore, an NSCLC cell line showed discontinuous deletions including either the CDKN2A or D9S171 locus. Therefore, the region surrounding the D9S171 locus was defined as another target region for the 9p21 deletions. It is possible that unknown tumor suppressor gene(s) are present in this chromosomal region. Genes Chromosomes Cancer 27:308-318, 2000.
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PMID:Two regions of homozygous deletion clusters at chromosome band 9p21 in human lung cancer. 1067 21

Germline mutations of the CDKN2A (p16(INK4A)) tumor suppressor gene predispose patients to melanoma and pancreatic carcinoma. In contrast, mutations of the murine CDKN2A gene predispose BALB/c mice to pristane-induced plasmacytoma. We describe here a family in which a germline mutation of CDKN2A is present in 4 individuals who developed melanoma as well as in a fifth family member who is suffering from multiple myeloma. To determine whether the CDKN2A mutation predisposed the myeloma patient to her disease, we carried out loss of heterozygosity studies on sorted bone marrow from this individual and observed loss of the wild type CDKN2A allele in the malignant plasma cells. We suggest that germline mutations of CDKN2A may predispose individuals to a wider variety of malignancy than has been hitherto reported, but that the expression of these cancers may depend heavily on the genetic background of the patient. (Blood. 2000;95:1869-1871)
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PMID:Germline CDKN2A mutation implicated in predisposition to multiple myeloma. 1068 50

The tumor suppressor gene CDKN2A is functionally inactivated, through mutations, deletions, or methylation, in a large variety of primary neoplasms as well as tumor cell lines. The CDKN2A locus gives rise to two distinct transcripts. P16INK4 and P19ARF. Because it has been shown that the disruption of only P19arf-coding sequences in mice is sufficient for tumor development, this transcript most likely also encodes a tumor suppressor. We have analyzed the two CDKN2A transcripts in fifteen human primary liver carcinomas, two human hepatoma cell lines, and five rodent hepatoma cell lines. No homozygous deletions of P19ARF and P16INK4 were found in these samples, whereas the normal P19arf transcript was absent in two of the five rodent cell lines (nonexpressed in one case and mutated in another). These results suggest that functional abrogation of P19ARF is not a primary event in hepatocarcinogenesis.
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PMID:Alterations of P19ARF in rodent hepatoma cell lines but not in human primary liver cancer. 1070 81

In this study, we examined the methylation status of the CDKN2A gene in patients with different forms of adult T-cell leukemia (ATL) using Southern blot analysis, methylation-specific PCR (MSPCR), and nucleotide sequencing. We found that the CDKN2A gene was more frequently methylated in fresh tumor cells isolated from patients with acute ATL (47%) or lymphoma-type ATL (73%) than in those with less malignant chronic (17%) and smoldering (17%) ATL. In addition, deletions of the CDKN2A gene were found in 24% of acute ATL patients; thus, abnormalities of the CDKN2A gene totaled 71% in acute ATL patients. In contrast, no CDKN2A gene methylation was found in asymptomatic carriers or uninfected individuals. Methylation of the p15 gene was not found in any samples from 36 ATL patients. Direct sequencing of the CDKN2A gene after sodium bisulfite treatment of genomic DNA revealed that the methylation of CpG sites had occurred in 24 of 32 ATL cases (75%) including chronic and smoldering ATL, even when MSPCR and the Southern blot had failed to detect CDKN2A gene methylation. Among fresh ATL samples with methylation, methylation was detected in the promoter region and exon in 17 of 24 cases, and methylation in the exon without promoter region was detected in 7 of 24 cases. In one case, the pattern of methylation proved to be different between peripheral blood cells and lymph node cells, suggesting the presence of multiple subclones with regard to methylation patterns, despite the same HTLV-I integration site. Quantitative PCR showed a marked decrease in CDKN2A mRNA expression in the cells with a methylated CDKN2A gene, especially if the promoter region was methylated. These findings suggest that CpG methylation decreases CDKN2A expression and represents a critical factor in the disease progression of ATL.
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PMID:Increasing methylation of the CDKN2A gene is associated with the progression of adult T-cell leukemia. 1070 22

Recent data suggest that additional factors, other than UV radiation, are involved in the etiology of non-melanoma skin cancer. These include alterations in the tumor suppressor genes, p53, p16$L*I*U$LINK4a$L*I$L/CDKN2A, p21$L*I*U$LWAF1/CIP1$L*I$L and the PTCH gene, as well as cytokines. Papillomavirus infections have been implicated in the etiology of non-melanoma skin cancer. The interaction of tumor suppressor genes and cytokines with the oncoproteins of high-risk mucosal HPV types have been studied in detail, but very little is known about the cutaneous HPV types. We have studied the effect of UV radiation on the URRs of HPV 1, 2, 3, 5, 7, 20, 23, 27, 38, 41, and 77. Neither the CAT-expression and promoter activity of these HPV types, nor presence or absence of wild-type or mutated p53 in the cell lines used, could be related to the DNA sequence homology between the different HPV types or their biological behavior.
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PMID:Human papillomaviruses in non-melanoma skin cancer. 1071 88

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized that unselected patients with both primary cancers, i.e., pancreatic cancer and malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourteen patients, with both pathologically verified pancreatic adenocarcinoma and melanoma, were assessed for germline CDKN2A mutations by polymerase chain reaction amplification and sequencing of six overlapping fragments encompassing exons 1alpha and 2. A yeast two-hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: I49S, a novel substitution in exon 1alpha, and M53I, a previously reported missense mutation in exon 2. Both variants lead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations. This finding has important implications not only for the proband, but also for other family members.
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PMID:Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. 1071 65


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