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NF2 Mutations and Meningiomas National Institute of Health Consensus Development Conference Statement on Neurofibromatosis (1987) Neurofibromatosis Res Newslett 3:]-6 Rouleau GA, Mere! P, lutchman M, Sanson i\f, Zucmanj, Marineau C, Hoang-Xuan K, et a\ (199]) Alterations in.\ new gene encoding a putative membrane-organizing protein causes neuro-fihromatosis type 2. Nature 36]:515- 521 Rouleau GA, Seizinger HR, Wertelecki W, Haines jl, Superneau OW, Martuza RL, Gusella jF (1990) Flanking markers bracket the neurofibromatosis type 2 (NF2) gene on chromosome 22. Am J Hum Genet 46:]2]-]28 Russell OS, Rubinstein Lj (1989) Pathology of tumours of the nervous system, 5th cd. Edward Arnold, london Sachs AB (1993) Messenger RNA degradation in eukaryotes. Cell 74:413-421 Sci zinger BR, De La Monte S, Atkins t, Gusella jF, l'o.-1artUz.1 RL (1987a) .Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc Nat! ACJ.d Sci USA 84:5419-5423 Seizinger BR, MartUz.1 RL, GusclbJF (1986) loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 322:644-647 Selzinger BR, Rouleau G, Ozilius Lj, Lane AH, St George H)'slop P, Huson S, Gusella jl; (1987b) Common pathogenetic mechanism for three tumor types in hilateral acoustic neurofibromatosis. Science 236:317-319 Sheffield VC, Beck )S, Kwilek AE, Sandstrom DW, SlOne EM (1993) The sensitivity of single-strand conformation pol}' morphism analysis for the detection of single base substitutions. Genomics 16:]25-3]2 Trofatter jA, MacCollin MM, Rutter Jl, Murrell JR, Duyao lI.H', Parry DM, Eldridge R, et al (199]) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 mmor suppressor. Cell 72:79J-800 \'l/ood MW, White Rj, Kernohan j\,\1 (1957) One hundred intracranial meningiomas (ound incidentally at necropsy. J Neuropathol Exp NeuroI16:]37~]40 Zang KD (1982) Cyw!ogical and cytogenctkal studies on human meningioma. Cancer Genet Cytogenet 6:249-274 zulch KJ (1979) Histological typing of tumoucsQf the central nen'ous system. World Health Organization, Geneva 160
Summary and Discussion Meningioma is a common benign central nervOllS system tumor (eNS) arising from arachnoidal cells surrounding the brain and spinal cord. Cytogenetic studies as early as 1967 and molecular genetic analyses revealed that loss of chromosome 22 is the most frequent aberration observed in these tumors. In additioll, 50% of the patients with the autosomal dominant inherited disorder NF2 have meningiomas. Linkage analysis in affected families has assigned the predisposing gene to chromosome 22. This indicates that both NF2 and sporadic meningioma presumably are the result of mutations in one Of more genes on chromosome 22. Consistent and specific chromosome deletions suggest the involvement of tumor suppressor genes. A tumor suppressor gene plays a role in tumorigenesis when both alleles of the gene are'inactivated. Loss of such a gene is one of the mechanisms involved in functional inactivation. Therefore, a ttlillor suppressor gene(s) on chromosome 22 is (are) probably involved in the development of meningiomas. The goal of the work described in this thesis was to localize and isolate this (these) gene(s) on chromosome 22. In order to identify the region(s) on chromosome 22 responsible for meningioma development we first collected meningiomas for cytogenetic and DNA analysis. At that time only a limited number of markers from this chromosome were available. Therefore, a chromosome 22 specific phage library was used for the isolation of additional probes. The 25 isolated singlecopy probes were further characterized by testing whether they recognized restriction fragment length polymorphisms (RFLPs) on human genomic DNA and they were regionally localized on chromosome 22 using a panel of somatic cell hybrids. The polymorphic probes were used to construct a linkage map (Chapter II). These probes and markers obtained from other laboratories were subsequently used to investigate our collection of meningiomas. Chapter III describes the results of the combined cytogenetic and molecular genetic study in OLlr series of meningiomas. Furthermore, the observed chromosomal changes were compared with other patient and tumor characteristics and statistically analyzed. In accordance with other reports loss of chromosome 22 was most frequently observed. We found complete or partial loss of this chromosome in 71 % of the tumors. Statistical analysis revealed a signiticant association between the number of 161
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GENES ON CHROMOSOME 22 INVOLVED IN
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PROMOTmCOMMIssm Promotor: Prof. Dr.
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Contents List of abbreviations 9 Ch
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List of abbreviations APC bp DCC FA
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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
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is that this interaction inactivate
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endogenous wt p53 by forming mixed
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Recent studies in these families ha
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In about 15% of all colon tumors an
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e explained by assuming that the nu
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3.6 The NFl gene Neurofibromatosis
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4 MENINGIOMA 4.1 Cells of origin In
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fossa and foramen magnum), convexit
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early cell cultures the presence of
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gene (Dumanski et aI., NNFF consort
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et aI., 1991b; Larsson et aI., 1990
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6 References Aaltonen LA, Peltomiik
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(1988) SV40 large tumor antigen for
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Haber DA, Buckler AJ, Glaser T, Cal
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carcinomas. Genes Chrom Cancer 2:19
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Pelletier J, Breunin~ W, Kashtan CE
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Stratton MR, Darling J, Lantos PL,
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Chapter II Isolatioll alld characte
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SHORT COMMUNICATION TABLE 1 Charact
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Appendix A lIew polymorphic probe 0
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Nudeic Acids Research, Vol. 19, No.
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Chapter III Cytogenetic, molecular
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Introduction Meningiomas are consid
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defined by evaluating 6 histologica
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number of clonal chromosomal abnorm
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#22 status No. Sex/Age (yr) Site of
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#22 slattls No. SexiAge (yr) Site o
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#22 status No. Sex/Age (yr) Site of
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Table 2. Comparison of FISH, cytoge
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No. Days in Karyotypes andlor clona
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No. Days in Karyotypes and/or clona
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to map both breakpoints (data not s
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Statistical analyses concerning age
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Tuble 4. Frequency tables between d
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from adult patients, indicating tha
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Acknowledgements This study was sup
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McDermid HE, Duncan AMV, Higgins MJ
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Chapter IV Familial anaplastic epen
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Familial anaplastic ependymoma: evi
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PATIENT A, born 1977, presented at
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Microscopic examination (patients A
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(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
Page 123 and 124: to playa role in the development of
Page 125 and 126: total sheared human genomic DNA bef
Page 127 and 128: Genomic cosmid contig spanning the
Page 129 and 130: probe A is conserved in hamster DNA
Page 131 and 132: Southerll, 1l0l1hern blots and evol
Page 133 and 134: The evolutionary conservation of th
Page 135 and 136: A " l ... aGAP~RAGC EPOV~SR~AGQGE ;
Page 137 and 138: postulates that the first AUG codon
Page 139 and 140: Bijlsma EK, Brouwer~Mladin R, Bosch
Page 141 and 142: Tanaka N, Nishisho I, Yamamoto 1'.1
Page 143 and 144: Chapter VII Constitutional DNA-leve
Page 145 and 146: GENES, CHROMOSOMES & CANCER 9;124-1
Page 147 and 148: LfKANNf DfPREZ fT AL TABLE I. Cytog
Page 149 and 150: LEKANNE DEPRF2 ET AL could be that
Page 151 and 152: Chapter VIII Frequent NF2 gene tran
Page 153 and 154: Am.'. HIIIII. Gellet. 54:1022-1029,
Page 155 and 156: Lekanne Deprez ct al. Table I Oligo
Page 157 and 158: Table 2 Nfl Gene-Transcript Mutatio
Page 159: Lebnne Deprez et lli. observed at a
Page 163 and 164: translocation (Chapter V). These hy
Page 165 and 166: were derived from patients with mor
Page 167 and 168: Samenvatting Meningeomen zUn goedaa
Page 169 and 170: het gebied rondom het MNI gen te be
Page 171 and 172: Curriculum vitae 30 juni 1965 gebor
Page 173 and 174: List of publications I) van 't Veer
Page 175 and 176: Nawoord Dit boekje is 101 sland gek
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