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human papillary thyroid carcinomas this gene showed rearrangements (Grieco et aI., 1990). The RET gene encodes a transmembrane tyrosine kinase protein with an as yet unknown ligand. In the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2 (MEN 2A and B), familial medullary carcinoma (FMTC) , and the dominantly inherited Hirschsprung's disease, which is a developmental disorder, specific mutations have been found in the RET proto-oncogene (Donis-Keller et aI., 1993; Mulligan et aI., 1993a; Edery et aI., 1994; Hofstra et aI., 1994; Romeo et aI., 1994). MEN 2 and FMTC are characterized by the development of bilateral medullary thyroid carcinoma (MTC). In both MEN 2A and B pheochromocytomas are observed and in MEN 2B a distinct more aggressive and complex phenotype is apparent (Nanes and Catherwood, 1992). Hirschsprung's disease is characterized by congenital absense of parasympathetic innervation in the lower intestinal tract and cancer-association has never been described. The mutations observed in the RET gene might explain the distict clinical phenotypes. The MEN2A and FMTC mutations were aU missense mutations involving the 4 conserved cysteines in the extracellular region and probably interfere with ligand binding (Donis-Keller et aI., 1993; Mulligan et aI., 1993a,b). In MEN2B all mutations found so far were specific threonine to methionine substitutions in codon 918 in the intracellular tyrosine kinase domain of RET. The same mutation was also observed in 6 sporadic MTC tumors (Hofstra et aI., 1994). The nature of the mutations found in Hirschsprung's disease however are different. These include deletions, nonsense and missense mutations and are presumably loss of function mutations. The RET mutations observed in the cancer syndromes suggest that the gene is an oncogene rather than a tumor suppressor gene because: 1) very specific heterozygous amino acid substitutions were observed and 2) chromosome 10 allelic loss was hardly ever found in these tumors (Landsvater et aI., 1989; Nelkin et aI., 1989; Mulligan et aI., 1993a,b). However, the observation that the RET protein dimerizes (Bongarzone et aI., 1993; Rodriguez and Park, 1993) suggests that a dominant-negative mechanism can not be ruled out. The presumed loss of function mutations found in Hirschsprung's disease indicate that haplo-insufficiency (dosage-effect) is the underlying mechanism. Homozygous RET gene knockout mice die soon after birth and show impairment in kidney development and lack enteric neurons throughout the digestive tract (Schuchardt et aI., 1994). 28
3.6 The NFl gene Neurofibromatosis type I (NFl), also known as von Recklinghausen neurofibromatosis, is an autosomal dominant disorder with a heterogeneous clinical manifestation (Riccardi, 1981). The hallmarks of NF I are: cutaneous or subcutaneous neurofibromas, cafe au lait spots and Lisch nodules. The NFl gene, located on chromosome 17q11.2, was isolated in 1990 and encodes a 2,818 amino acid protein (Cawthon et ai., 1990; Viskochil et ai., 1990; Wallace et ai., 1990). The gene product, neurofibromin, shares high homology with GTPase activator proteins (Buchberg et ai., 1990; Xu et ai., 1990a; Xu et ai., 1990b). The protein may function as a negative regulator of the p21'''-mediated signal transduction pathway andlor down stream of p21'~ (Bollag and McCormick, 1992). The possible interaction of neurofibromin with microtubules suggests a role in mitosis and cell division (Seizinger, 1993). NFl gene mutations were observed in sporadic tumors that are also found in NFl patients (neurofibroma, neurofibrosarcoma, pheochromocytoma and astrocytoma), but in addition in neuroblastoma, malignant melanoma, a sporadic colon carcinoma and myelodysplastic syndrome, diseases that do not occur in NFl patients (Li et ai., 1992). Recent data suggest that the NFl gene functions at least in some of the tumors as a recessive tumor suppressor gene, because homozygous deletions in the NFl locus have been found in a neurofibrosarcoma from a NF 1 patient, some melanomas and some neuroblastomas (Andersen et ai., 1993; Johnson et ai., 1993; Legius et ai., 1993). 3.7 The NF2 gene Neurofibromatosis type 2 displays an autosomal dominant inheritance and is genetically linked to chromosome 22 (Rouleau et ai., 1990). The hallmark for this disease is the development of bilateral schwannomas of the eighth cranial nerve. Apart from this, multiple spinal and intracranial schwannomas and meningiomas may appear in these patients (Evans et ai., 1992a). Recently two independent groups have isolated the NF2 gene, which encodes a 595 amino acid protein, called merlin (moesin-ezrin-radixin like protein, Trofatter et aI., 1993) or schwannomin (Rouleau et ai., 1993). High homology of the N-terminal 340 residues of this protein to the cytoskeleton associated proteins moesin, ezrin and radixin suggests a 29
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 and 16: transformation came from somatic ce
Page 17 and 18: 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: e explained by assuming that the nu
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
Page 76 and 77: #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
Page 96 and 97:
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
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Am. J. HI/m. Genet. 48:783-790, 199
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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
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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
Page 141 and 142:
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
Page 175 and 176:
Nawoord Dit boekje is 101 sland gek
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