UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The evidence for human tumor suppressor genes is reviewed. Initial evidence was provided by somatic cell hybridization, where somatic cell hybrids derived from the fusion of malignant and normal parental cells were found to be transformed but nontumorigenic. Tumorigenic segregants appeared at later intervals and were associated with the loss of specific normal chromosomes. Evidence for loss of tumor suppressor genes in many human malignancies was provided by a combination of cytogenetic and restriction fragment length polymorphism analyses. Functional analyses, using monochromosome transfer from normal cells into cancer cells, have confirmed the existence of suppressor genes and their critical role in control of tumor formation. Recently, the tumor suppressor gene Rb-1 has been cloned and also shown to have tumor-suppressing properties. Most recently, a candidate tumor suppressor gene on chromosome 17 (p53) has been implicated in colorectal carcinomas and other human malignancies. It is of interest to note that this gene was originally described as an oncogene. The biological mechanism of tumor suppression has been linked to the induction of differentiation in both somatic cell hybrids and osteosarcoma cells transfected with the normal Rb-1 gene. However, recent studies with monochromosome transfer into neuroblastoma cells indicates that differentiation may be dissociated from tumor suppression. Tumor suppressor genes do not act directly as negative regulators of conventional "dominantly-acting" oncogenes and therefore cannot be considered as anti-oncogenes in the sense of directly interacting with and regulating the expression of such oncogenes as ras and myc. However, it is speculated that they may negatively regulate an, as yet undiscovered, family of oncogenes which would not be dominantly expressed.
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PMID:The evidence for human tumor suppressor genes. 257 36

We reported previously that loss of heterozygosity (LOH) on chromosomes 2q, 9p and 18q frequently occurs in neuroblastoma and that patients with 9p LOH in the tumors showed statistically significant association with an advanced stage of the disease and poor prognosis. To determine the role of chromosome 9 loss in neuroblastoma, we performed deletion mapping of chromosome 9 in 80 cases of neuroblastoma using 11 polymorphic microsatellite markers and a restriction fragment length porymorphism marker. LOH at one or more loci on chromosome 9 was detected in 33 of 80 cases (41%). Chromosome 9p was lost in 24 of 80 cases (32%), whereas chromosome 9q was lost in 18 of 80 cases (23%). There were two commonly deleted regions mapped to 9p21 between the D9S171 marker and the IFNB1 marker and 9q34-qter distal to the D9S176 marker. In addition, patients with LOH at 9p21 but not at 9q34-qter in the tumors showed statistically significant association with poor prognosis (P = 0.023). Because the commonly deleted regions at 9p21 includes the p16 (CDKN2A) gene, the status of the p16 gene was further examined in 80 fresh tumors and 19 cell lines of neuroblastoma. A missense mutation was detected at codon 52 in a fresh tumor. The p16 gene was not expressed in 13 of 19 cell lines (72%), and 5 of the 13 cell lines displayed methylation of the CpG island surrounding the first exon of the p16 gene. These results suggest that the p16 gene is a candidate tumor suppressor gene for neuroblastoma, and its inactivation may contribute to the progression of neuroblastoma.
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PMID:Deletion map of chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma. 904 Nov 93

DCC (deleted in colorectal cancer), a candidate tumor suppressor gene located in chromosome band 18q21.2, encodes a transmembrane protein of 1447 amino acids. Neogenin, a protein with nearly 50% amino acid identity to DCC, was recently identified because of its dynamic expression in the developing nervous system and gastrointestinal tract of the chicken. To explore a role for the human neogenin (NGN) gene in cancer, we have isolated cDNAs for two alternatively spliced forms of NGN, encoding proteins of 1461 and 1408 amino acids. Fluorescence in situ hybridization studies (FISH) localized NGN in chromosome band 15q22, a region infrequently affected by alterations in cancer. NGN transcripts of about 7.5 and 5.5 kb were detected in all adult tissues studied. In contrast to the frequent loss of DCC expression, no alterations in NGN expression were observed in more than 50 cancers studied, including glioblastoma, medulloblastoma, neuroblastoma, colorectal, breast, cervical and pancreatic cancer cell lines and xenografts. Based on their sequence conservation and similar expression during development, DCC and NGN may have related functions. However, the chromosomal location and ubiquitous expression of NGN in various human tumors suggest it is infrequently altered in cancer.
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PMID:Identification and characterization of neogenin, a DCC-related gene. 912 61

Loss of heterozygosity (LOH) on chromosome 18q21 is found frequently in various human cancers. Three candidate tumor suppressor genes, DCC (deleted in colorectal carcinomas), DPC4 (deleted in pancreatic carcinomas, locus 4), and MADR2/JV18-1 (MAD-related gene 2), have been cloned and identified from this chromosome region. We have reported recently that LOH on chromosome 18q is observed frequently in neuroblastoma. Alterations of DCC are involved in many human tumors. DPC4 and MADR2/JV18-1 are recently demonstrated to be altered in pancreatic and colorectal cancers, respectively. To confirm if inactivation of the DCC, DPC4, and MADR2/JV18-1 genes is involved in the pathogenesis of neuroblastoma and to clarify the mechanism of inactivation, we analyzed the expression of DCC, DPC4, and MADR2/JV18-1 in neuroblastoma cell lines and primary tumors by reverse transcription-PCR and investigated the mutations in the coding regions of these genes by PCR/reverse transcription-PCR single-strand conformation polymorphism. We found that 12 of 25 (48%) cell lines and 14 of 32 (44%) primary tumors, including 3 with 18q LOH, had absent or reduced expression of DCC mRNA. Expression was more likely to be reduced in advanced (67%) than in early stage neuroblastomas (24%) (P = 0.036), suggesting that inactivation of the DCC gene plays an important role in the progression of neuroblastoma. Altered expression of DPC4 was found in six (24%) cell lines and six (19%) tumors. MADR2/JV18-1 expression was reduced or absent only in four (16%) cell lines and three (9%) tumors. Mutations of the DCC genes were examined in 25 of 29 exons in neuroblastoma cell lines, and those exons in which mutations were found were further examined in primary tumors. We found missense mutations of AAC (Asn) to AGC (Ser) at DCC codon 176 in one cell line and ACC (Thr) to ATC (Ile) at codon 1105 in one cell line and tumor, respectively; polymorphisms of CGA (Arg) to GGA (Gly) at codon 201 and TTT (Phe) to TTG (Leu) at codon 951 in most of the cell lines and tumors; and a silent mutation of GAG (Glu) to GAA (Glu) at codon 118 in four cell lines and five primary tumors. We did not identify any mutations in the DPC4 and MADR2/JV18-1 genes in neuroblastoma. Our results suggested that mutations of the DCC gene may be involved in the pathogenesis of neuroblastomas but failed to account for the relatively high frequency of the altered expression, implying that other mechanisms are responsible for the inactivation of the DCC gene in neuroblastoma. Low frequency of reduced or absent mRNA expression and lack of mutations in DPC4 and MADR2/JV18-1 genes suggested a limited role for these two genes in neuroblastoma.
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PMID:Expression and mutational analysis of the DCC, DPC4, and MADR2/JV18-1 genes in neuroblastoma. 928 86

Deletions and translocations resulting in loss of distal 1p-material are known to occur frequently in advanced neuroblastomas. Fluorescence in situ hybridisation (FISH) showed that 17q was most frequently involved in chromosome 1p translocations. A review of the literature shows that 10 of 27 cell lines carry 1;17 translocations. Similar translocations were also observed in primary tumours. Together with the occurrence of a constitutional 1;17 translocation in a neuroblastoma patient, these observations suggest a particular role for these chromosome re-arrangements in the development of neuroblastoma. Apart from the loss of distal 1p-material, these translocations invariably lead to extra copies of 17q. This also suggested a possible role for genes on 17q in neuroblastoma tumorigenesis. Further support for this hypothesis comes from the observation that in those cell lines without 1;17 translocations, other chromosome 17q translocations were present. These too lead to extra chromosome 17q material. Molecular analysis of 1;17 translocation breakpoints revealed breakpoint heterogeneity both on 1p and 17q, which suggests the involvement of more than 2 single genes on 1p and 17q. The localisation of the different 1p-breakpoints occurring in 1;17 translocations in neuroblastoma are discussed with respect to the recently identified candidate tumor suppressor regions and genes on 1p. In this study, we focused on the molecular analysis of the 17q breakpoints in 1;17 translocations. Detailed physical mapping of the constitutional 17q breakpoint allowed for the construction of a YAC contig covering the breakpoint. Furthermore, a refined position was determined for a number of 17q breakpoints of 1;17 translocations found in neuroblastoma cell lines. The most distal 17q breakpoint was identified in cell line UHG-NP and mapped telomeric to cosmid cCI17-1049 (17q21). This suggests that genes involved in a dosage-dependent manner in the development of neuroblastoma map in the distal segment 17q22-qter. Future studies aim at the molecular cloning of 1;17 translocation breakpoints and at deciphering the mechanisms leading to 1;17 translocations and possibly to the identification of neuroblastoma genes at or in the vicinity of these breakpoints.
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PMID:Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes. 951 36

DCC, a candidate tumor suppressor gene from chromosome 18q21, is most highly expressed in the developing nervous system. In vitro studies suggest a role for DCC in neuronal differentiation, and 18q allelic loss occurs in a subset of neuroblastomas. To address the hypothesis that loss of DCC function may contribute to tumorigenesis in cells of neural origin, we utilized a combination of RNase protection, immunoblotting, and immunohistochemical approaches to characterize DCC expression in 62 primary neuroblastomas and 16 neuroblastoma cell lines. The DCC protein was undetectable in 38% of the primary tumors and 56% of the cell lines. Of note, primary tumors lacking DCC expression were more likely to have been obtained from patients with disseminated or stage D disease (P = 0.01). In addition, loss of DCC expression was observed in three of six primary tumors from stage DS patients. No consistent relationship between the loss of DCC expression and N-myc amplification was observed in our studies. Our findings suggest that loss of DCC expression may contribute to the dissemination of neuroblastoma cells, perhaps through alterations in growth and differentiation pathways distinct from those regulated by N-myc.
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PMID:Loss of DCC expression in neuroblastoma is associated with disease dissemination. 981 73

Distal alterations of the short arm of chromosome 1 are among the most frequent cytogenetic abnormalities in human breast carcinoma. We studied 96 primary human breast carcinomas for allelic imbalance using a panel of 31 polymorphic microsatellite, restriction fragment length polymorphism, and variable number of tandem repeat markers located mainly in the 1p32-pter region. Allelic imbalance at one or more loci was observed on the short arm of chromosome 1 in 56 (58.3%) of the 96 tumors. The 56 1p-altered tumor DNAs showed loss of heterozygosity (LOH), 12 (21.4%) at all informative loci tested and 44 (78.6%) at some loci. The LOH pattern of these 44 partially deleted tumors identified two distinct consensus regions of deletion on 1p32-pter (1p36.3 and 1p32). These regions match those described by other investigators but are considerably smaller. The 1p32 band is located within one of the two 1p regions of LOH in neuroblastoma, suggesting the involvement of the same unidentified tumor suppressor gene in both human breast cancer and neuroblastoma. The candidate tumor suppressor genes TNFR2, RIZ, DAN, RAP1GA1, FGR, MDGI, EXTL, and hRAD54 were excluded from the two consensus regions of deletion identified at 1p32-pter. Analysis of six polymorphic markers chosen to map within the other deleted regions described in breast tumors confirmed that two additional breast tumor suppressor genes are located in the proximal part (1p22 and 1p13) of chromosome arm 1p. Taken together, these results suggest that several unknown suppressor genes on 1p might be involved in the development of breast cancer. The refinement of the regions of LOH to within a few cM, and the recent publication of transcript maps of the human genome, mean that candidate genes and expressed sequence tags mapping to these deleted regions can now be investigated.
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PMID:Deletion mapping of chromosomal region 1p32-pter in primary breast cancer. 1045 6

Human chromosome 11q23.2 has been proposed to contain a tumor suppressor gene(s) whose deletion has been associated with cancer of the lung and breast and with neuroblastoma. To analyze the genomic structure and to isolate a candidate tumor suppressor gene from this region, we constructed a 2-Mb sequence-ready contig map using bacteriophage P1 (P1), bacterial artificial chromosome (BAC), and P1-derived artificial chromosome (PAC). The map comprises a contig of 24 overlapping P1, BAC, and PAC clones. To isolate gene fragments from the region, we performed direct cDNA library screening, exon trapping, EST mapping, and genomic sequencing using the P1, BAC, and PAC clones. Sequence analysis of 5 clones, which spans 23% (458,738 bp) of the region, and extensive gene scanning along the entire region revealed that the region is extraordinarily scarce in genes, but we identified one ubiquitously expressed novel gene and one testis-specific gene fragment. The novel gene, which we call IGSF4 (immunoglobulin superfamily 4), is transcribed into a 1.6- or 4.4-kb RNA encoding a 442-amino-acid protein. It shares strong homology with mouse IGSF-B12 and cell adhesion molecules NCAM1 and NCAM2 within their Ig-like C2-type domains. The IGSF4 gene, a novel gene that is shown to be located in the common loss of heterozygosity region, possesses a number of interesting features and may be good candidate for a tumor suppressor gene.
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PMID:A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2. 1061 Jul 5

The distal region of a short arm of chromosome 1p is frequently deleted in many human cancers including neuroblastoma (NBL), in which it has been narrowed down to the smallest region of overlap between D1S244 and D1S214 (approximately 7 cM). During the search for the candidate tumor suppressor genes mapped within the region, we found the KIAA0591 gene which encoded a new human kinesin-related protein with a homology to human axonal transporter of synaptic vesicles (ATSV). The kinesin is an intracellular motor protein and often associated with neuronal differentiation and survival. Here we identified a complete open reading frame of the KIAA0591 gene by screening a cDNA library derived from human substantia nigra. The KIAA0591 protein contains a possible pleckstrin homology (PH) domain at its carboxy-terminus. However, it did not possess a force-generating motor domain which is well conserved among kinesin superfamily members (KIFs). Northern blot analysis demonstrated that KIAA0591 mRNA was preferentially expressed in both adult and fetal brains, kidney, skeletal muscle and pancreas. KIAA0591 was expressed in favorable NBLs at higher levels than in unfavorable NBLs, although RT-PCR SSCP analysis showed no mutation within the coding region of the KIAA0591 gene, when 8 neuroblastoma tissues and 15 neuroblastoma-derived cell lines were examined. Thus, the full-length KIAA0591 gene may be a novel member of human KIF superfamily which lacks motor domain and might function as a tumor suppressor in an epigenetic but not a classic Knudson's manner.
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PMID:Identification of the full-length KIAA0591 gene encoding a novel kinesin-related protein which is mapped to the neuroblastoma suppressor gene locus at 1p36.2. 1076 26

Recently, loss of heterozygosity (LOH) studies suggest that more than two tumor suppressor genes lie on the short arm of chromosome 1 (1p) in neuroblastoma (NB). To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in 20 NB cell lines using a high-density STS map spanning chromosome 1p36, a common LOH region in NB. We found that the 45-kDa subunit of the DNA fragmentation factor (DFF45) gene was homozygously deleted in an NB cell line, NB-1. DFF45 is the chaperon of DFF40, and both molecules are necessary for caspase 3 to induce apoptosis. DFF35, a splicing variant of DFF45, is an inhibitor of DFF40. We examined 20 NB cell lines for expression and mutation of DFF45 gene by reverse transcription (RT)-polymerase chain reaction (PCR) and RT-PCR-single-strand conformation polymorphism. Some novel variant transcripts of the DFF45 gene were found in NB cell lines, but not in normal adrenal gland and peripheral blood. These variants may not serve as chaperons of DFF40, but as inhibitors like DFF35, thus disrupting the balance between DFF45 and DFF40. No mutations of the DFF45 gene were found in any NB cell line, suggesting that the DFF45 is not a tumor suppressor gene for NB. However, homozygous deletion of the DFF45 gene in the NB-1 cell line may imply the presence of unknown tumor suppressor genes in this region.
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PMID:DNA fragmentation factor 45 (DFF45) gene at 1p36.2 is homozygously deleted and encodes variant transcripts in neuroblastoma cell line. 1142 Jul 52

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