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Discussion Characterization of the reciprocal t(4;22)(pI6;qll) in meningioma 32 has led to the identification of a new gene, consisting of at least two exons of about 4.7 kb (5' end) and 2.8 kb (3' end). The entire 5' exon and genomic sequences upstream (results not shown) are extremely GC rich. This area apparently is a very large GC island. The translocation breakpoint is located in the 5' exon, which strongly suggests that the gene is directly involved in the tumorigenesis of meningioma 32. Therefore, we have called this gene MNl, for candidate meningioma gene I. Many reports describe the use of reciprocal translocations for the isolations of cancer genes. Specific chromosomal translocations are involved in the activation of proto-oncogenes as is the case in many leukemias (Solomon et aI., 1991). In addition, they can also inactivate a tumor suppressor gene. For instance, in neurofibromatosis type I (NFl) two reciprocal translocations involving band 17ql1.2 resulted in the successful isolation of the NFl tumor suppressor gene (Cawthon et aI., 1990; Viskochil et aI., 1990; Wallage et aI., 1990). In agreement with the observed loss of chromosome 22 in meningiomas this might suggest that the MNl gene is a tumor suppressor gene and that the translocation in meningioma 32 inactivates the gene. Northern blot analysis of meningioma 32 RNA supports this. Southern blot analysis of71 meningiomas with probes from the MNI region revealed a point mutation and a 1.5 kb homozygous deletion in one tumor (55). This tumor was from a patient with multiple meningiomas. Further analysis showed that the alterations were found also in the gennline of this patient and were located about 10 kb downsteam of the MNl gene (I.ekanne Deprez et aI., 1994a). One might speculate that these alterations interfere with MNl gene function. However, this gene was highly expressed in meningioma 55. Northern analysis of the MNl gene in other meningiomas also showed high expression in some and low or no expression at all in others. This might indicate that the expression of the MNl gene is deregulated in meningiomas. Further study at the protein level is however needed to investigate this in more detail. Although the nucleotide sequence as we have obtained so far would suggest 2 possible ORFs, in vitro transcription/translation experiments suggest that only one large protein of approximately 3.8 kb is formed (Molyn et aI., personal communication). Therefore, we expect that both ORFs are part of this large protein and that some sequence artifacts are still present in the I kb that separate them. The scanning model for the initiation of translation 136
postulates that the first AUG codon in the mRNA located in the right context defines the beginning of the protein (Kozak, 1991). Therefore, we expect that the methionine at position 53 (Fig.6B), which is the first AUG with a reasonable Kozak sequence, is the start point for translation. Be
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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
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
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: A " l ... aGAP~RAGC EPOV~SR~AGQGE ;
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 and 160: Lebnne Deprez et lli. observed at a
Page 161 and 162: Summary and Discussion Meningioma i
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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