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5 Scope of the thesis
Cytogenetic analysis and LOR studies of meningioma tumors points to the localization of (a)
tumor suppressor gene(s) on the long arm of chromosome 22 because:
in about 50% of the tumors one copy of chromosome 22 is lost and this is often the sole
chromosomal abnormality and
in a few percent of the cases additional aberrations concerning chromosome 22, such as
translocations (aU in band qll,q12) and partial loss of the long arm are found.
The purpose of this thesis was to identify and characterize (a) tumor suppressor gene(s),
which (is) are involved in the pathogenesis of meningioma. To reach this goal we started
with the isolation and characterization of single-copy probes for chromosome 22 (Chapter II).
Cytogenetic analysis and genotype analysis of the tumors were carried out in order to identify
the chromosomal aberrations in the tumors. Furthermore, other patient and tumor
characteristics were investigated and mutuaUy compared (Chapter Ill). The same approach
was used to study the involvement of chromosome 22 in a patient with familial anaplastic
ependymoma (Chapter IV). ]n order to localize a meningioma tumor suppressor gene on
chromosome 22 we took advantage of a meningioma (MN32) in which a reciprocal
t(4;22)(pI6;qll) had occurred. We hypothesized that this translocation disrupts a potential
tumor suppressor gene. To map this translocation breakpoint on chromosome 22 we made
hybrid ceUlines in which both reciprocal translocation products were segregated in different
hybrids (Chapter V). Long-range restriction mapping was used to further characterize the
breakpoint. One probe (D22S 193) recognized the translocation breakpoint on pulsed field
gels. Chromosome walking towards the translocation breakpoint and searching for transcribed
sequences in this region resulted in the isolation of the MNI gene (Chapter VI). Probes from
this region were used to investigate DNA from other meningiomas and blood of a patient
with multiple meningiomas. Southern blot analyses observed aberrant restriction fragments
in DNA isolated from a patient with multiple meningiomas (patient 55). The characterization
of these alterations are described in chapter VII. Findings from other groups (see 4.6), the
isolation of the MNI gene and the recent cloning of the NF2 gene (Rouleau et aI., 1993;
Trofatter et aI., 1993) raise a question about the relative contribution of these genes/loci in
the development of meningiomas. To investigate the extent in which the NF2 is involved we
performed mutation analysis of the NF2 gene transcript in our series of (mostly) sporadic
meningiomas, including tumors 32 and 55 (Chapter VIII).
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