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defined by evaluating 6 histological parameters (loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, focal necrosis and brain infiltration). This resulted in three different grades: grade I (benign), grade II (atypical), and grade III (anaplastic). The grading o[ the meningiomas was carried out by one of us (SZS). The anatomic sites of tumor origin were subdivided in convexity (C), base (B), falx (F), and intraventricular (IV). Cytogenetic analysis and in sitll hybridization: Cytogenetic analysis was carried out on cultured samples, from passage a (pO) corresponding to the first outgrowth of cells to passage 3 (p3). Cytogenetic results were only taken into account when the cells were cultured for less than 50 days. Cells were harvested and fixed according to standard methods. Chromosomes were identified using RFA, QFQ and GTG banding techniques and described according to ISCN (1991). Fluorescent in situ hybridization (FISH) was performed on interphase nuclei directly obtained from the fresh tumor sample or after short term culture. Competitive in situ hybridization was applied using at least two chromosome 22 specific cos mid or centromere probes following the technique as reported by Arnoldus et al. (1991). For all probes used, the number of signals per nucleus after hybridization was counted in at least 100 nuclei. As a control, 34 lymphocyte cultures of the patients (when available) and 23 lymphocyte cultures of normal donors were used. In both control groups we observed similar hybridization results: one spot (apparent monosomy) in about 5 % of nuclei and two spots (disomy) in more than 90% of the nuclei. This allowed us to conclude the absence of constitutional loss of chromosome 22 in patients lymphocytes. Control data were lIsed to determine the sensitivity of the technique used and to define the cut off rate (mean % of nuclei with one spot + two times the standard deviation) of 13.5% and 12%, respectively above which a cell popUlation with (partial) monosomy could be safely identified. The following probes cited from centromere to telomere of chromosome 22 were used: p22!l:2.1 (centromere, McDermid et al. 1986); 2 cosmids in the lambda immunoglobulin light chain gene region: lambda 2.2, lambda 3.1 (Goyns et al., 1984); 4 cos mid probes 40D2, 58B12, 50BII, 76A4 ordered from centromere to telomere within 100 kb from D22S193 (Chapter VI); 29B5 (D22S72); 103DI2 (D22S56); 4 cosmid probes in the NF2 region: 115D7 (NEFH), 121G 10, 96CIO, 74BI. The cosmid probes in the vicinity of 70
D22S193, D22Sn, D22S56 and NF2 were obtained by screening two chromosome 22- specific cosmid libraries (LL22NCOI and LL22NC03: de Jong et aI., 1989; Zucman et aI., 1992). LOB analysis oj chromosome 22: High-molecular-weight DNA was isolated from stored tumor tissue according to standard procedures. Before DNA isolation the percentage of tumor cells was determined by microscopic examination of a cryostat section of the tumor specimen. Only tumor samples with more than 80% tumor cells were used for DNA analysis. Most specimens contained more than 90% tumor cells. When available, constitutional DNA was isolated from peripheral blood leucocytes. Restriction endonuclease digestion, agarose gel electrophoresis, Southern transfer, hybridization to 32p labeled probes and autoradiography were performed as reported (Lekanne Deprez et aI., 199Ia). The following DNA markers for loci on chromosome 22 were used: D22S181, 022S183 (Lekanne Deprez et aI., 199Ib), D22SIO (Hofker et aI., 1985), D22S182 (Lekanne Deprez et aI., 199Ib), D22S1 (Barker et aI., 1984), D22S193 (Lekanne Deprez et aI., 199Ib), 17.13'(3 prime part of the MNI eDNA 17.1, which detects a Pvu II polymorphism, unpublished result), D22S29 (Rouleau et aI., 1989), D22S45 (Budarf et aI., 1991), 022S201 (Lekanne Deprez et aI., 1991c) and D22S205 (van Biezen et aI., 1993). D22S201 and 022S205 are located distal to D22S193, but their orientation relative to each other or D22S45 is not known. The other probes are ordered from centromere to telomere. For most of the tumor DNA samples analyzed in this study constitutional ONA was not available, therefore loss of heterozygosity (LOH) for a specific marker was assumed when a heterozygous DNA sample showed clear reduction of intensity of one of the 2 alleles. SlatiSlics: The statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) and with the Epidemiological Graphics, Estimation, and Testing package (EGRET). We used the X' test, the Exact Homogeneity test, and Fisher's exact test. A significant association was concluded when P '" 0.05. The following variables were mutually analyzed: the sex of the patients, the age at surgery (over and under 50 years of age), the site of tumor origin, the histological subtype, the grade, the loss of (parts of) chromosome 22, and the 71
Page 1:
GENES ON CHROMOSOME 22 INVOLVED IN
Page 4 and 5:
PROMOTmCOMMIssm Promotor: Prof. Dr.
Page 6 and 7:
Contents List of abbreviations 9 Ch
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List of abbreviations APC bp DCC FA
Page 13 and 14:
1 Cancer is a genetic disease It is
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transformation came from somatic ce
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to tumorigenesis if a mutation inac
Page 19 and 20: is that this interaction inactivate
Page 21 and 22: endogenous wt p53 by forming mixed
Page 23 and 24: Recent studies in these families ha
Page 25 and 26: In about 15% of all colon tumors an
Page 27 and 28: e explained by assuming that the nu
Page 29 and 30: 3.6 The NFl gene Neurofibromatosis
Page 31 and 32: 4 MENINGIOMA 4.1 Cells of origin In
Page 33 and 34: fossa and foramen magnum), convexit
Page 35 and 36: early cell cultures the presence of
Page 37 and 38: gene (Dumanski et aI., NNFF consort
Page 39 and 40: et aI., 1991b; Larsson et aI., 1990
Page 41 and 42: 6 References Aaltonen LA, Peltomiik
Page 43 and 44: (1988) SV40 large tumor antigen for
Page 45 and 46: Haber DA, Buckler AJ, Glaser T, Cal
Page 47 and 48: carcinomas. Genes Chrom Cancer 2:19
Page 49 and 50: Pelletier J, Breunin~ W, Kashtan CE
Page 51 and 52: Stratton MR, Darling J, Lantos PL,
Page 53: Chapter II Isolatioll alld characte
Page 56 and 57: SHORT COMMUNICATION TABLE 1 Charact
Page 59: Appendix A lIew polymorphic probe 0
Page 62 and 63: Nudeic Acids Research, Vol. 19, No.
Page 65: Chapter III Cytogenetic, molecular
Page 68 and 69: Introduction Meningiomas are consid
Page 72 and 73: number of clonal chromosomal abnorm
Page 74 and 75: #22 status No. Sex/Age (yr) Site of
Page 76 and 77: #22 slattls No. SexiAge (yr) Site o
Page 78 and 79: #22 status No. Sex/Age (yr) Site of
Page 80 and 81: Table 2. Comparison of FISH, cytoge
Page 82 and 83: No. Days in Karyotypes andlor clona
Page 84 and 85: No. Days in Karyotypes and/or clona
Page 86 and 87: to map both breakpoints (data not s
Page 88 and 89: Statistical analyses concerning age
Page 90 and 91: Tuble 4. Frequency tables between d
Page 92 and 93: from adult patients, indicating tha
Page 94 and 95: Acknowledgements This study was sup
Page 96 and 97: McDermid HE, Duncan AMV, Higgins MJ
Page 99 and 100: Chapter IV Familial anaplastic epen
Page 101 and 102: Familial anaplastic ependymoma: evi
Page 103 and 104: PATIENT A, born 1977, presented at
Page 105 and 106: Microscopic examination (patients A
Page 107 and 108: (Lekanne Deprez et aI., 1994). Tabl
Page 109 and 110: Chapter V A t(4;22) ill a meningiom
Page 111 and 112: Am. J. HI/m. Genet. 48:783-790, 199
Page 113 and 114: Putative Tumor-suppressor Gene in M
Page 119 and 120: Chapter VI Molecular clolling of a
Page 121 and 122:
Molecular Cloning of a Gene Disrupt
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to playa role in the development of
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total sheared human genomic DNA bef
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Genomic cosmid contig spanning the
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probe A is conserved in hamster DNA
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Southerll, 1l0l1hern blots and evol
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The evolutionary conservation of th
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A " l ... aGAP~RAGC EPOV~SR~AGQGE ;
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postulates that the first AUG codon
Page 139 and 140:
Bijlsma EK, Brouwer~Mladin R, Bosch
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Tanaka N, Nishisho I, Yamamoto 1'.1
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Chapter VII Constitutional DNA-leve
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GENES, CHROMOSOMES & CANCER 9;124-1
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LfKANNf DfPREZ fT AL TABLE I. Cytog
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LEKANNE DEPRF2 ET AL could be that
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Chapter VIII Frequent NF2 gene tran
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Am.'. HIIIII. Gellet. 54:1022-1029,
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Lekanne Deprez ct al. Table I Oligo
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Table 2 Nfl Gene-Transcript Mutatio
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Lebnne Deprez et lli. observed at a
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Summary and Discussion Meningioma i
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translocation (Chapter V). These hy
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were derived from patients with mor
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Samenvatting Meningeomen zUn goedaa
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het gebied rondom het MNI gen te be
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Curriculum vitae 30 juni 1965 gebor
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List of publications I) van 't Veer
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Nawoord Dit boekje is 101 sland gek
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