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particular (parts ot) chromosomes in human tumors. The latter approach uses the frequent occurrence of restriction fragment length polymorph isms (RFLPs) of some DNA probes or polymorphic microsatellites in the human genome. This technique takes advantage of the heterozygous state of a patient's normal (constitutional) DNA for a particular polymorphic marker, loss of that part of the chromosome is the case when tumor tissue of the same patient shows reduction or loss of one of the alleles (Fig. I). LOH study M ""rmol tumor M_ M- ,,- "",m&1 par, of ch,omolorn;>, tumor pal. of c~'omo'omu Soul""rn bioi Figure 1. The most commonly observed inactivation scheme for a recessive tumor suppressor gene. The normal (wild-type) copies of the tumor suppressor gene are shown with the open boxes. In the tumor both copies of the gene are inf'lctivated by a small mutation in one allele (black box) and loss of the portion of the chromosome that harbours the second allele. Loss of heterozygosity (LOH) of this chromosomal part can be detected on a Sonthern blot. This analysis uses the ability of a polymorphic DNA marker, specific for the relevant region of the chromosome, to detect both the maternal and paternal alleles (A I and A2). The comparison of normal and tumor DNA from the same individual can distinguish whether one allele is lost in the tumor. A comprehensive list of consistently observed allele losses in solid tumors has been described by Seizinger et al. (1991). A combination of linkage analyses in cancer families and LOH studies in both sporadic and familial tumors have led to the localization of a large number of (mostly) tumor suppressor gene loci. The 'positional cloning' (Collins, 1992) andlor candidate gene approach eventually resulted in the cloning of some of these genes. A number of examples are listed in Table 1. In the following sections these genes are briefly described. The products of tumor suppressor genes may be involved in the negative regulation of cell growth, induction of terminal differentiation and/or apoptosis. The gene can contribute 16
to tumorigenesis if a mutation inactivates the gene (Weinberg, 1989). Thus, the mutations are 'loss of function' mutations. Possible mechanisms involved are: (partial) loss of a chromosome, point mutations, small deletions or insertions, translocations and genomic imprinting. Table 1. Isolated tumor SUppl'essor genes Heritable cancer Chromosomal location Gene* Reference syndrome Retinoblastoma. 13ql4 Rbi Friend et aI., 1986: Osteosarcoma Fung et ai., 1987: ue et ai., 1987 Wilms' tumor lIpl3 IVTI Call et al.. 1990; Gessler et al.. 1990 Li·Fraumeni syndrome 17pl3 p53 Malkin et a1.. 1990 Familial adenomatous 5q21 APe Groden et aI., 1991; polyposis Joslyn et al .• 1991; Kinzler et a!., 1991b; Nishisho et al., 1991 5q21 Mee Kinzler et al., 1991a 18q21.3 Dee Fearon et al.. 1990a Hereditary non-polyposis 2pl6 hMSH2 Fishel et al •• 1993; colorectal cancer Leach et ai., 1993 3p21-23 hMLHl Bronner et aI., 1994 Neurofibromatosis type I 17qll NFl Cawthon et a!., 1990; Viskochil et al.. 1990; Wallace et al., 1990 Neurofibromatosis type 2 22ql2 NFl Rouleau et al.. 1993; Trofalter et a!., 1993 von Hippel-Lindau 3p25 VHL Latifetal.,1993 MUltiple endocrine 10qll RET Mulligan et al.. 1993a neoplasia 2 * All except the RET gene are examples of tumor suppressor genes. If a particular gene is thought to he the primary genetic event the gene and its chromosomal localization are written in bold letters. 17
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
Page 9: List of abbreviations APC bp DCC FA
Page 13 and 14: 1 Cancer is a genetic disease It is
Page 15: transformation came from somatic ce
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 70 and 71:
defined by evaluating 6 histologica
Page 72 and 73:
number of clonal chromosomal abnorm
Page 74 and 75:
#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
Page 88 and 89:
Statistical analyses concerning age
Page 90 and 91:
Tuble 4. Frequency tables between d
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from adult patients, indicating tha
Page 94 and 95:
Acknowledgements This study was sup
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McDermid HE, Duncan AMV, Higgins MJ
Page 99 and 100:
Chapter IV Familial anaplastic epen
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Familial anaplastic ependymoma: evi
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PATIENT A, born 1977, presented at
Page 105 and 106:
Microscopic examination (patients A
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(Lekanne Deprez et aI., 1994). Tabl
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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 115 and 116:
Page 117 and 118:
Page 119 and 120:
Chapter VI Molecular clolling of a
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Molecular Cloning of a Gene Disrupt
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to playa role in the development of
Page 125 and 126:
total sheared human genomic DNA bef
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Genomic cosmid contig spanning the
Page 129 and 130:
probe A is conserved in hamster DNA
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Southerll, 1l0l1hern blots and evol
Page 133 and 134:
The evolutionary conservation of th
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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
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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
Page 151 and 152:
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
Page 167 and 168:
Samenvatting Meningeomen zUn goedaa
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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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