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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
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