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Jan P Dumanski - One of the best experts on this subject based on the ideXlab platform.
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1p and 3p deletions in meningiomas without detectable aberrations of Chromosome 22 identified by comparative genomic hybridization
Genes Chromosomes and Cancer, 1997Co-Authors: Katrin M Carlson, Magnus Nordenskjold, Carl E G Bruder, Jan P DumanskiAbstract:Meningioma is a common tumor of the meninges covering the central nervous system. Although generally a benign tumor, meningioma often recurs and is malignant in 5-10% of all cases. Loss of Chromosome 22 loci, and specifically inactivation of the NF2 tumor suppressor gene, is considered one of several critical steps in the tumorigenesis of meningioma. However, cytogenetic and molecular investigations have failed to detect either aberrations of Chromosome 22 or mutations in the NF2 gene in approximately 40% of all tumors, thus making it apparent that an alternative mechanism(s) is responsible for the development of a large fraction of meningiomas. This subset of meningiomas is not distinct with regard to clinical and histopathological features from tumors showing deletions on Chromosome 22. It is, therefore, important to attempt the elucidation of molecular pathway(s) that may operate in the tumorigenesis of these tumors. We used comparative genomic hybridization (CGH) to identify regions of the genome other than Chromosome 22, contributing to the development of meningioma. We analyzed 25 tumors that had undergone detailed LOH analysis on Chromosome 22 and were shown to contain no detectable deletions. Two benign, malignancy grade I, meningiomas showed concurrent deletion of 1p and 3p. These results suggest that loss of both 1p and 3p may contribute to meningioma tumorigenesis. This may represent genetic changes that are alternative to deletions on Chromosome 22.
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isolation and mapping of cosmid markers on human Chromosome 22 including one within the submicroscopically deleted region of digeorge syndrome
Human Genetics, 1994Co-Authors: Hiroki Kurahashi, Kenzo Akagi, Jan P Dumanski, Shin-ichiro Takai, Katsu Karakawa, Tsutomu Nakamura, Tetsuya Sano, Shintaro Okada, Isamu NishishoAbstract:A genomic cosmid library was constructed from a Chinese hamster/human hybrid cell containing human intact Chromosome 22 as its only human component. Of 1000 cosmids with inserts derived from human Chromosome 22, 191 were tested for restriction fragment length polymorphisms (RFLPs). As a result, 64 clones detected RFLPs, including five variable number of tandem repeats systems. Of the remaining 127 cosmids, 111 detected a single copy sequence on human Chromosome 22. Five somatic cell hybrids allowed us to assign all of the 64 polymorphic cosmids and 44 non-polymorphic cosmids to four different regions of human Chromosome 22. In two patients with DiGeorge syndrome, one of the cosmids that had been sublocalized to 22pter-q11 detected hemizygosity. These 108 cosmid markers regionally assigned to human Chromosome 22 should be useful for the construction of long-range physical maps and the identification of genetic alterations on the Chromosome.
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Deletions on Chromosome 22 in sporadic meningioma
Genes chromosomes & cancer, 1994Co-Authors: Martin H. Ruttledge, V. Peter Collins, Magnus Nordenskjold, Ya-gang Xie, Fei-yu Han, Myriam Peyrard, Jan P DumanskiAbstract:Meningiomas are the second most common group of primary central nervous system tumors in humans. Cytogenetic and molecular studies imply that genes involved in the primary development of meningioma reside on Chromosome 22. The recently characterized neurofibromatosis type 2 gene (NF2) has been shown to be mutated in two cases of sporadic meningioma, suggesting that this is the Chromosome 22 gene which is involved in tumorigenesis. We have investigated a series of 170 meningiomas by deletion mapping analysis with 43 markers from Chromosome 22 to ascertain if NF2 is the only gene on this autosome that is inactivated. Half of the tumors showed results consistent with monosomy for Chromosome 22, whereas 13 cases showed terminal deletions of 22q, including the NF2 region. Homozygous (complete) deletions were detected in tumors from two patients. In one of them complete loss was found at the NF2 locus and cosmid contigs from the region were used to determine the extent of the deletions. The second tumor showed homozygous loss of two large genomic regions outside the NF2 region. These aberrations were confined to only one part of this large tumor, suggesting that they may be involved in the later stages of meningioma development. An additional four tumors had interstitial deletions on Chromosome 22, in three of them without overlap with NF2. Our results show that NF2 is completely inactivated in sporadic meningioma but do not rule out the possibility that additional Chromosome 22 loci are important in tumorigenesis.
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Identification, characterisation and clinical applications of cosmids from the telomeric and centromeric regions of the long arm of Chromosome 22
Human genetics, 1994Co-Authors: Ya-gang Xie, Jan P Dumanski, Fei-yu Han, Svetlana Bajalica, Elisabeth Blennow, Ulf Kristoffersson, Magnus NordenskjoldAbstract:Using human telomeric repeats and centromeric alpha repeats, we have identified adjacent single copy cosmid clones from human Chromosome 22 cosmid libraries. These single copy cosmids were mapped to Chromosome 22 by fluorescence in situ hybridisation (FISH). Based on these cosmids, we established contigs that included part of the telomeric and subtelomeric regions, and part of the centromeric and pericentromeric regions of the long arm of human Chromosome 22. Each of the two cosmid contigs consisted of five consecutive steps and spanned approximately 100–150 kb at both extreme ends of 22q. Moreover, highly informative polymorphic markers were identified in the telomeric region. Our results suggest that the telomere specific repeat (TTAGGG)n encompasses a region that is larger than 40 kb. The cosmid contigs and restriction fragment length polymorphism markers described here are useful tools for physical and genetic mapping of Chromosome 22, and constitute the basis of further studies of the structure of the subtelomeric and pericentromeric regions of 22q. We also demonstrate the use of these clones in clinical diagnosis of different Chromosome 22 aberrations by FISH.
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A map of 22 loci on human Chromosome 22.
Genomics, 1991Co-Authors: Jan P Dumanski, V. Peter Collins, Magnus Nordenskjold, Beverly S Emanuel, Marcia L. Budarf, E. Carlbom, Heather E. Mcdermid, Roger K. Wolff, Peter O'connell, Ray WhiteAbstract:We constructed a genetic linkage map of the entire long arm of human Chromosome 22 with 30 polymorphic markers, defining 22 loci. The map consists of a continuous linkage group 110 cM long, when male and female recombination fractions are combined; average distance between the loci is 5.2 cM. All loci were placed on the map with high support against alternative orders (odds in excess of 1000:1). The order of loci presented in our map is in full agreement with that of the previous linkage maps of Chromosome 22 and with the physical assignment of markers. Two markers included in this map, KI-831 (D22S212) and pEFZ31 (D22S32), allowed us to better define the region of the (11;22) translocation breakpoint specific for Ewing sarcoma. Ten additional polymorphic markers were placed on the 22-loci map with odds lower than 1000:1 against alternative locations. In total, we have introduced 29 new markers on the linkage map of Chromosome 22.
Magnus Nordenskjold - One of the best experts on this subject based on the ideXlab platform.
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1p and 3p deletions in meningiomas without detectable aberrations of Chromosome 22 identified by comparative genomic hybridization
Genes Chromosomes and Cancer, 1997Co-Authors: Katrin M Carlson, Magnus Nordenskjold, Carl E G Bruder, Jan P DumanskiAbstract:Meningioma is a common tumor of the meninges covering the central nervous system. Although generally a benign tumor, meningioma often recurs and is malignant in 5-10% of all cases. Loss of Chromosome 22 loci, and specifically inactivation of the NF2 tumor suppressor gene, is considered one of several critical steps in the tumorigenesis of meningioma. However, cytogenetic and molecular investigations have failed to detect either aberrations of Chromosome 22 or mutations in the NF2 gene in approximately 40% of all tumors, thus making it apparent that an alternative mechanism(s) is responsible for the development of a large fraction of meningiomas. This subset of meningiomas is not distinct with regard to clinical and histopathological features from tumors showing deletions on Chromosome 22. It is, therefore, important to attempt the elucidation of molecular pathway(s) that may operate in the tumorigenesis of these tumors. We used comparative genomic hybridization (CGH) to identify regions of the genome other than Chromosome 22, contributing to the development of meningioma. We analyzed 25 tumors that had undergone detailed LOH analysis on Chromosome 22 and were shown to contain no detectable deletions. Two benign, malignancy grade I, meningiomas showed concurrent deletion of 1p and 3p. These results suggest that loss of both 1p and 3p may contribute to meningioma tumorigenesis. This may represent genetic changes that are alternative to deletions on Chromosome 22.
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Deletions on Chromosome 22 in sporadic meningioma
Genes chromosomes & cancer, 1994Co-Authors: Martin H. Ruttledge, V. Peter Collins, Magnus Nordenskjold, Ya-gang Xie, Fei-yu Han, Myriam Peyrard, Jan P DumanskiAbstract:Meningiomas are the second most common group of primary central nervous system tumors in humans. Cytogenetic and molecular studies imply that genes involved in the primary development of meningioma reside on Chromosome 22. The recently characterized neurofibromatosis type 2 gene (NF2) has been shown to be mutated in two cases of sporadic meningioma, suggesting that this is the Chromosome 22 gene which is involved in tumorigenesis. We have investigated a series of 170 meningiomas by deletion mapping analysis with 43 markers from Chromosome 22 to ascertain if NF2 is the only gene on this autosome that is inactivated. Half of the tumors showed results consistent with monosomy for Chromosome 22, whereas 13 cases showed terminal deletions of 22q, including the NF2 region. Homozygous (complete) deletions were detected in tumors from two patients. In one of them complete loss was found at the NF2 locus and cosmid contigs from the region were used to determine the extent of the deletions. The second tumor showed homozygous loss of two large genomic regions outside the NF2 region. These aberrations were confined to only one part of this large tumor, suggesting that they may be involved in the later stages of meningioma development. An additional four tumors had interstitial deletions on Chromosome 22, in three of them without overlap with NF2. Our results show that NF2 is completely inactivated in sporadic meningioma but do not rule out the possibility that additional Chromosome 22 loci are important in tumorigenesis.
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Identification, characterisation and clinical applications of cosmids from the telomeric and centromeric regions of the long arm of Chromosome 22
Human genetics, 1994Co-Authors: Ya-gang Xie, Jan P Dumanski, Fei-yu Han, Svetlana Bajalica, Elisabeth Blennow, Ulf Kristoffersson, Magnus NordenskjoldAbstract:Using human telomeric repeats and centromeric alpha repeats, we have identified adjacent single copy cosmid clones from human Chromosome 22 cosmid libraries. These single copy cosmids were mapped to Chromosome 22 by fluorescence in situ hybridisation (FISH). Based on these cosmids, we established contigs that included part of the telomeric and subtelomeric regions, and part of the centromeric and pericentromeric regions of the long arm of human Chromosome 22. Each of the two cosmid contigs consisted of five consecutive steps and spanned approximately 100–150 kb at both extreme ends of 22q. Moreover, highly informative polymorphic markers were identified in the telomeric region. Our results suggest that the telomere specific repeat (TTAGGG)n encompasses a region that is larger than 40 kb. The cosmid contigs and restriction fragment length polymorphism markers described here are useful tools for physical and genetic mapping of Chromosome 22, and constitute the basis of further studies of the structure of the subtelomeric and pericentromeric regions of 22q. We also demonstrate the use of these clones in clinical diagnosis of different Chromosome 22 aberrations by FISH.
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A map of 22 loci on human Chromosome 22.
Genomics, 1991Co-Authors: Jan P Dumanski, V. Peter Collins, Magnus Nordenskjold, Beverly S Emanuel, Marcia L. Budarf, E. Carlbom, Heather E. Mcdermid, Roger K. Wolff, Peter O'connell, Ray WhiteAbstract:We constructed a genetic linkage map of the entire long arm of human Chromosome 22 with 30 polymorphic markers, defining 22 loci. The map consists of a continuous linkage group 110 cM long, when male and female recombination fractions are combined; average distance between the loci is 5.2 cM. All loci were placed on the map with high support against alternative orders (odds in excess of 1000:1). The order of loci presented in our map is in full agreement with that of the previous linkage maps of Chromosome 22 and with the physical assignment of markers. Two markers included in this map, KI-831 (D22S212) and pEFZ31 (D22S32), allowed us to better define the region of the (11;22) translocation breakpoint specific for Ewing sarcoma. Ten additional polymorphic markers were placed on the 22-loci map with odds lower than 1000:1 against alternative locations. In total, we have introduced 29 new markers on the linkage map of Chromosome 22.
Juan A. Rey - One of the best experts on this subject based on the ideXlab platform.
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Loss of Chromosome 22 and absence of NF2 gene mutation in a case of multiple meningiomas.
Human pathology, 2002Co-Authors: Jesus Lomas, M. Josefa Bello, Josém. De Campos, M.elena Kusak, J.l. Sarasa, M. Eva Alonso, Pilar Gonzalez-gomez, Dolores Arjona, Juan A. ReyAbstract:Multiple meningiomas are rare, and only 13 cases have been subjected to molecular genetic analysis to detect mutations of the tumor-suppressor gene neurofibromatosis type 2 (NF2) located on Chromosome 22. Most of these cases display NF2 gene mutations parallel to loss of the Chromosome 22 homolog, indicating that inactivation of this gene may represent an early event in the development of multiple meningiomas. We report a case of a 61-year-old woman who developed multiple (dorsal and intracranial) meningiomas. Cytogenetic and molecular genetic studies demonstrated the loss of a copy of Chromosome 22 in the 5 meningiomas studied and the absence of NF2 gene mutations in 4 of those available for this molecular analysis. These findings, together with similar data from 2 previously reported cases, suggest the participation of a tumor-suppressor gene other than NF2 on Chromosome 22 in the pathogenesis of a subgroup of multiple meningiomas.
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Chromosome 22 heterozygosity is retained in most hyperdiploid and pseudodiploid meningiomas
Cancer genetics and cytogenetics, 1993Co-Authors: M. Josefa Bello, Juan A. Rey, Josém. De Campos, Jesús Vaquero, M.elena Kusak, J.l. Sarasa, Angel PestañaAbstract:Hyperdiploid or pseudodiploid modal Chromosome numbers were found characterizing six human meningiomas, and all six tumors were disomic for Chromosome 22. The scarce previous reports on the subject suggest that, in these cytogenetic subgroups of meningiomas, duplication of the retained Chromosome 22 occurs after the loss of the other member of the pair, thus correlating well with the main characteristic of meningiomas, that is, losses of 22. To verify this question, molecular genetic analyses were performed on DNA pairs from blood and tumoral samples of all six cases, using polymorphic markers for Chromosome 22. Restriction fragment length polymorphism studies failed to show any loss of heterozygosity for markers located on this Chromosome in all six cases, suggesting that a different mechanism to that previously proposed might take place in the hyperdiploid or pseudodiploid meningiomas; perhaps a submicroscopic involvement (microdeletions or inactivating mutations) of the meningioma locus (both alleles) may result in an effect similar to that produced by monosomy 22 (which probably unmasks recessive mutations on the retained allele), enhancing the development of meningiomas.
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Abnormalities of Chromosome 22 in human brain tumors determined by combined cytogenetic and molecular genetic approaches
Cancer genetics and cytogenetics, 1993Co-Authors: Juan A. Rey, M. Josefa Bello, Josém. De Campos, Jesús Vaquero, M.elena Kusak, J.l. Sarasa, Angel PestañaAbstract:Southern blot hybridization studies were performed on a panel of 130 blood/tumor samples from brain neoplasms including all major histologic subtypes: 50 meningiomas, 18 neurinomas, 56 gliomas, and six others. To detect abnormalities involving Chromosome 22, polymorphic probes were used to analyze eight loci located in this Chromosome: D22S9, IGLV, D22S20, D22S32, MB, PDGF-B, D22S80, and D22S171. Loss of heterozygosity (LOH) was observed in 40 cases including monosomy, terminal, and interstitial deletions, which suggest the location of recessive tumor genes in certain Chromosome 22 subregions (22q11.3-q12 in neurinomas and meningiomas, and 22q13 in malignant gliomas). Cytogenetic studies were performed in parallel on the same tumors, in most instances corroborating the presence of abnormalities for Chromosome 22. Nevertheless, discrepancies between the cytogenetic and molecular findings were observed in several cases, suggesting that the use of both methodologies in combination might provide key information on the incidence and extent of the abnormalities involving Chromosome 22 in human brain tumors.
D R Cox - One of the best experts on this subject based on the ideXlab platform.
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analysis of Chromosome 22 deletions in neurofibromatosis type 2 related tumors
American Journal of Human Genetics, 1992Co-Authors: R K Wolff, Kelly A Frazer, Robert K Jackler, Michael J Lanser, Lawrence H Pitts, D R CoxAbstract:The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on Chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, we have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on Chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of Chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, we identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model.
James F. Gusella - One of the best experts on this subject based on the ideXlab platform.
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Mapping of a human A2a adenosine receptor (ADORA2) to Chromosome 22.
Genomics, 1994Co-Authors: Mia Maccollin, Robert A. Peterfreund, Marcy E. Macdonald, J. Stephen Fink, James F. GusellaAbstract:Using a probe derived from the recently cloned rat A2a receptor A2aR, a panel containing multiple human-rodent somatic cell hybrids was probed by Southern hybridization. A faint but specific signal was seen in the Chromosome 22-only line. A human Chromosome 22 cosmid library (LL22NC02, Lawrence Livermore Library) was then screened by Southern hybridization to the same probe; two cosmid clones (54C4 and 30D1) were isolated. Several restriction digests of both cosmids were rehybridized with the rat A2aR probe, and a 700-bp PstI fragment that specifically hybridized to the probe was subsequently cloned into plasmid Bluescript II. This subclone, designated pHUAD2, was then hybridized to a panel of 60 human-rodent somatic cell hybrid lines digested with SacI to address the possibility of related genes or pseudogenes located on other Chromosomes. Two human bands of approximately 3 and 4 kb were seen in a total of four hybrid lines; two of these lines contain only Chromosome 22. Although a previous report had suggested that the human A2a receptor resided on human Chromosome 11 with a related sequence on human Chromosome 11 with a related sequence on human Chromosome 10, hybrids containing human Chromosomes 10 and 11 did not hybridize to the probe.
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A Set of STS Assays Targeting the Chromosome 22 Physical Framework Markers
Genomics, 1993Co-Authors: Mia Maccollin, Guy A Rouleau, Beverly S Emanuel, Marcia L. Budarf, Bertrand Fontaine, James A. Trofatter, Anil G. Menon, Donna M. Romano, Christopher T. Denny, James F. GusellaAbstract:Abstract The widespread use of the sequence-tagged site (STS) as a quick, efficient, and reproducible assay for comparing physical and genetic map information promises to facilitate greatly long-range goals of time mapping of the human genome. We have designed 21 STS assays for loci on human Chromosome 22. These assays primarily tag the physical framework markers of the long arm of 22, but additional assays have been designed from known genes and loci in the neurofibromatosis 2 (NF2) region. The availability of these assays will make these loci available to the research community without physical transfer of materials and will serve as start points for further efforts to physically map Chromosome 22 with yeast artificial Chromosome clones.
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Loss of Chromosome 22 alleles in human sporadic spinal schwannomas
Annals of neurology, 1991Co-Authors: Bertrand Fontaine, Mark P. Hanson, Robert L. Martuza, James F. GusellaAbstract:Acoustic neuromas occur either as sporadic solitary tumors in the general population or as inherited bilateral tumors typically in patients with neurofibromatosis type 2. Loss of heterozygosity for markers on the long arm of Chromosome 22 has been reported in both instances, and neurofibromatosis type 2 has been genetically linked to a marker on the long arm of this autosome, suggesting that a unique locus on Chromosome 22 is implicated in tumorigenesis of both sporadic and inherited acoustic neuromas. To determine whether the locus for neurofibromatosis type 2 might also be responsible for tumorigenesis of those schwannomas distinct from acoustic neuromas in people without neurofibromatosis type 2, we studied the DNA content of three sporadic spinal schwannomas. In all three, we found loss of heterozygosity for at least three markers on the long arm of Chromosome 22, indicating a partial or total monosomy 22 in the tumor. Our results suggest that a locus on Chromosome 22 is responsible for tumorigenesis in schwann cells regardless of their location in the central nervous system, and that some other mechanism (genetic or nongenetic) might account for the relative high proportion of schwannomas developing from the eighth cranial nerve.