Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate the p16 gene alterations in nasopharyngeal carcinoma (NPC), we have examined for mutations and deletions of the p16 gene in samples of NPC including 3 cell lines, 3 xenografts, and 20 primary tumors with matched blood DNA as controls. Using single-strand conformation polymorphism and direct sequencing analysis, no p16 gene mutations were detected in the NPC primary tumors and xenografts. Mutations of the p16 gene were found in three NPC cell lines, but no normal allele was present in these samples. Homozygous deletion of the p16 gene has been identified in 2 (67%) of 3 cases of NPC xenografts and 7 (35%) of 20 cases of primary tumors by comparative multiplex PCR analysis. A homozygous deletion region distal to the p16 locus was observed in a case of NPC primary tumor. Our data document for the first time that alterations of the p16 gene were frequent in NPC and that homozygous deletion was the major mechanism for the inactivation of this gene. These findings suggest that complete inactivation of the p16 gene may play a role in the development of NPC. Moreover, inactivation of other putative tumor suppressor gene(s) outside of the p16 locus within chromosome 9p21-22 may also contribute to the pathogenesis of this disease.
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PMID:p16 gene alterations in nasopharyngeal carcinoma. 774 98

Four sets of cell lines (UM-SCC-14A, -14B, and -14C; UM-SCC-17A and -17B; UM-SCC-81A and -81B; and UM-SCC-83A and -83B), established from primary and metastatic or locally recurrent tumors from four patients with squamous cell carcinoma of the head and neck, were examined for loss of heterozygosity (LOH) on chromosome 18q. Metastatic or recurrent cell lines from all four exhibited 18q LOH. UM-SCC-14A, -14B, and -14C, which were derived from locally recurrent (14A and 14B) and metastatic (14C) tumors, lost all of 18q. However, in the other three cases, there was a partial loss of 18q in the recurrent or metastatic tumor cell lines but not in the primary tumor cell lines from the same patient. To determine whether the cell lines accurately reflect in vivo loss of 18q, we analyzed matched sets of normal, tumor, and tumor cell line DNA from eight patients with squamous cell carcinoma of the head and neck, including the tumor tissue corresponding to UM-SCC-81B. Three of the additional seven tumors and cell lines had 18q LOH. For all eight cases in which tumor and corresponding cell line DNAs were analyzed, there was complete concordance between allelic loss in the tumor and allelic loss in the corresponding cell line. The common region of loss established by tumors and cell lines with partial loss includes 18q21-18qter. This region contains the putative tumor suppressor gene DCC and two Mad (Mothers against dpp)-related genes, DPC4 and MADR2, which are both components in a transforming growth factor-beta-like signaling pathway. Loss of 18q in metastatic and locally recurrent tumors, but not in primary tumors from the same patients, suggests that a tumor suppressor gene in this region may be important in the progression of squamous cell carcinoma.
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PMID:Evidence that loss of chromosome 18q is associated with tumor progression. 904 Nov 79

A putative tumor suppressor, PTEN/MMAC1 gene at 10q23 was recently identified and found to be mutated in many different human tumors. To determine the role of the PTEN/MMAC1 gene in lung cancer, we screened 34 small cell lung cancer (SCLC) cell lines, 10 SCLC tumors, 13 non-small cell lung cancer (NSCLC) cell lines and 10 NSCLC tumors using Denaturing HPLC (DHPLC) and direct sequencing methods. In SCLC, six (18%) of the cell lines and one of the primary tumor samples (10%) showed alterations of the PTEN/MMAC1 gene including point mutations, small fragment deletions, and homozygous deletions. All of the point mutations and small fragment deletions were observed in hemizygously deleted cell lines. In contrast to SCLC, none of the NSCLC tumors or cell lines had mutations in the PTEN/MMAC1 gene. These data indicate that PTEN/MMAC1 mutations contribute to the pathogenesis and neoplastic evolution in SCLC but not in NSCLC.
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PMID:PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. 969 41

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.
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PMID:Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability. 1062 Jan 9

Loss of heterozygosity (LOH) on 18q predicts poor survival in head and neck squamous cell carcinomas (HNSCCs). Several putative tumor suppressor genes, such as DCC, DPC4/Smad4, and MADR2/Smad2, are mapped to 18q, but thus far, the important gene locus in HNSCC is not known. To identify possible gene loci on 18q, we performed LOH studies using tumor DNA from 57 HNSCC primary tumor cell lines and DNA isolated from fibroblasts or lymphoblastoid cells from the same patients. Forty-two highly polymorphic microsatellite markers spaced not more than 5 cM apart (mean distance, 1.82 cM) spanning the region from D18S44 in 18q11.1 to D18S1141 in 18q23 were used. D18S71 in 18p11.21 on 18p was also used to determine whether the short arm was retained. Forty-three of 57 (75%) HNSCC lines showed LOH or isolated allelic imbalance (AI) for at least one locus on 18q. Although many of the cell lines had large distal 18q deletions with a breakpoint between 18q11.1 and 18q12.2 to qter, three loci were identified that were lost in 70% or more of the cases. The minimally lost regions (MLRs) range in size from 1.5-15.79 cM. The most proximal is centered on D18S39 (1.56 cM) in band 18q21.1, with LOH or isolated AI in 28 of 38 (74%) of informative cases. The largest (15.8 cM) begins at D18S61 (28 of 40; 70%) in band 18q22.2 and extends through D18S50 in 18q23. The third is centered on D18S70 (30 of 40; 75%) in band 18q23 (3.67 cM). Of these MLRs, only the one centered on D18S39 has been implicated previously in HNSCC. D18S70, the most frequently lost marker, was the only marker consistently lost in three tumor cell lines with very minimal losses, UM-SCC-19, UM-SCC-67, and UM-SCC-73A. In addition, UM-SCC-91 exhibited AI only at this locus, and UT-SCC-4 had AI at D18S70 and D18S39 only. Close physical mapping of these three regions may pinpoint one or more previously unidentified tumor suppressor genes.
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PMID:Identification of new minimally lost regions on 18q in head and neck squamous cell carcinoma. 1091 46

Genetic alterations of the long arm of chromosome 11 have been implicated in melanoma pathogenesis, and we recently identified two distinct regions of common allelic loss in chromosomal band 11q23. To establish the point in time of melanoma tumorigenesis at which these two putative tumor suppressor loci become relevant, we investigated allelic loss [loss of heterozygosity (LOH)] in both chromosomal regions in tumors of progressing patients. We analyzed 102 tumor samples from 23 patients for whom at least two (10 patients) or three (13 patients) tumor samples from different clinical progression steps (such as primary tumor and/or in-transit metastasis and/or regional lymph node metastasis and/or distant metastasis) were available. We detected no 11q23 LOH at any stage in 3 of 23 patients and detected LOH at all stages tested in 8 of 23 patients. In 8 of the remaining 12 (67%) patients with 11q23 LOH at some stage during tumor progression, we found this to occur first at regional lymph node metastasis. Two of these patients retained constitutional heterozygosity in several in-transit metastases that developed up to 7 months after lymph node metastases that already had loss. We therefore conclude that 11q23 LOH is associated with regional lymph node metastasis in melanoma. Finally, we detected an allele shift restricted to a histomorphologically distinct part of a primary melanoma and found that the same parental chromosome was affected by allelic loss in a subsequently occurring lymph node metastasis. These findings support our conclusion and give additional evidence for the hypothesis of molecular heterogeneity of early tumor cell populations in melanoma.
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PMID:11q23 allelic loss is associated with regional lymph node metastasis in melanoma. 1095 7

Aberrant methylation of promoter CpG regions is a putative mechanism whereby tumor suppressor genes are inactivated. We used a candidate gene approach to investigate the patterns and significance of this epigenetic change in natural killer (NK) cell malignancies. Thirty-three patients were studied for promoter methylation in five putative tumor suppressor genes by methylation-specific polymerase chain reaction (MSP), which has a sensitivity of 10(-3). The p73 gene was methylated in 94% of cases, a frequency that is the highest known for any human malignancy. In the NK cell lymphoma line NK92, p73 was also completely methylated, and the p73 transcript was correspondingly not detectable by quantitative polymerase chain reaction. Treatment of the cell line with 5-azacytidine, a demethylation reagent, led to demethylation of the p73 promoter and reinduction of p73 gene expression. These results suggested that promoter CpG methylation might be an important mechanism in suppressing p73 gene expression in NK cells. Other methylated genes included hMLH1 (63%), p16 (63%), p15 (48%), and RAR beta (47%). Methylation of two or more genes occurred in 88% of cases. With promoter methylation as a molecular marker, MSP identified two cases of occult marrow metastasis. Interestingly, the primary tumor and metastasis showed different methylation patterns, implying that separate clonal evolutions might have occurred at these sites. Furthermore, MSP also identified tumor infiltration in random oropharyngeal biopsies in a case where histological examination could not show evidence of tumor involvement. We conclude that NK cell malignancies show a specific pattern of promoter methylation, with p73 being consistently involved. These results suggest that p73 may be an important target in the neoplastic transformation of NK cells, and the demonstration of its methylation may serve as a potential molecular tool for NK cell lymphoma detection.
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PMID:Specific patterns of gene methylation in natural killer cell lymphomas : p73 is consistently involved. 1178 99

Frequent allelic imbalances, including loss of heterozygosity (LOH) and microsatellite instability (MSI), have been found on the long arm of chromosome 21 (21q) in several types of human cancer. This study was designed to identify the tumor suppressor locus (or loci) associated with oral squamous cell carcinoma (SCC) on 21q. In order to understand the details of genetic alterations on chromosome 21, we performed polymerase chain reaction analysis of microsatellite polymorphisms corresponding to ten loci on this chromosome. We examined forty primary tumor tissues, forty corresponding normal tissues, and seven lymph node metastatic tissues. We identified novel tumor suppressor loci in this region in primary oral SCCs. To further determine the role of 21q deletions in oral cavity carcinogenesis, forty oral SCCs were examined for allelic imbalances (LOH or MSI) at 21q using ten microsatellite markers. Among these forty patients, twenty-six (65%) showed LOH at one or more loci. Deletion mapping of these tumors revealed four discrete, commonly deleted regions on the chromosome arm. Furthermore, we detected MSI in seventeen of those tested cases (42.5%). We compared our results with the clinicopathologic features. A number of sites displaying LOH at 21q could be detected in early stage lesions, and the frequencies of LOH tended to be higher in later clinical stages, but no statistical correlation was observed. Our results strongly suggest that allelic imbalances on 21q are involved in the development of oral SCC and that at least four different putative tumor suppressor genes contributing to the pathogenesis of this disease are present on 21q. Furthermore, allelic loss on 21q appears to be a useful indicator for evaluating the malignancy and prognosis of oral SCC, because the LOH of recurrent cases was more frequent than that of non-recurrent ones.
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PMID:Allelic imbalance on the long arm of chromosome 21 in human oral squamous cell carcinoma: relationship between allelic imbalances (LOH and MSI) and clinicopathologic features. 1191 98

Melanoma development and progression is thought to be the result of a multi-step accumulation of genetic damage, with loss of heterozygosity in chromosome 9p (MTS1) frequently described. In addition, chromosome 10q allelic loss has been reported, implicating the tumor suppressor gene PTEN/MMAC1 on 10q23.3. The MXI1 gene at 10q24-25 is another candidate tumor suppressor that has only rarely been studied in melanomas, with conflicting results. We used microdissection-based genotyping to investigate 29 melanomas from 20 patients for loss of heterozygosity in intragenic and flanking microsatellite markers for this latter gene. Concurrently, the MTS1 gene was similarly studied using two flanking microsatellites. Fifty-four percent (15 of 28) of the informative cases showed loss of heterozygosity for one or both MXI1 markers, as compared with 67% (16 of 24) of the informative cases for MTS1. MXI1 allelic loss was seen more frequently in recurrent/metastatic tumors (59%), as compared with in primary (33%) lesions. Eighty percent of the primary tumors showed loss of heterozygosity for MTS1, as well as 63% of recurrent/metastatic ones. We studied more than one tumor in eight patients, with those from three patients showing discordant genetic patterns. One patient showed a metastatic tumor with allelic loss for MXI1 that was not identified in the primary melanoma or a local recurrence. The other two patients showed clonal heterogeneity in MXI1 at synchronous and metachronous metastatic foci. These findings support MXI1 as a putative tumor suppressor gene involved in conventional melanoma progression. Genetic heterogeneity seen in different metastases from the same primary suggests a nonlinear pattern of chromosomal damage, with the development of multiple clones within the primary tumor, each acquiring its own metastatic potential.
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PMID:Loss of heterozygosity in the MXI1 gene is a frequent occurrence in melanoma. 1455 81

High frequency loss of 3p21.3 region is a common event in various kinds of tumors including nasopharyngeal carcinoma (NPC). RASSF1A has been identified as a putative tumor suppressor gene residing in this region. Chromosome alterations and epigenetic changes are commonly observed as mechanisms for inactivation of RASSF1A function. In this study, we applied the PCR-cloning-sequencing strategy to examine somatic mutations in RASSF1A in NPC tissues as compared with the sequences detected in the matched peripheral blood lymphocytes. Our results revealed a high incidence of RASSF1A mutation in primary tumor tissues of NPC. There are totally 35 mutations identified in 74% (17/23) of these NPC cases, including 30 transitions, three transversions and two deletions. Most of these mutations result in amino acid changes: three nonsense (stop codon) mutations, two-1 bp deletion (frameshift), 26 missense and the remaining four are synonymous (silent). No obvious 'hot-spot' mutations were observed in this study. A similarly high rate (74%) of promoter methylation of RASSF1A was also detected in the same group of NPC tissues, but no significant correlation between mutation and methylation was detected. Our results suggest various mechanisms involved in inactivation of RASSF1A function and indicate a critical role of RASSF1A in NPC development.
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PMID:High frequency somatic mutations in RASSF1A in nasopharyngeal carcinoma. 1622 21


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