The genotypes were analyzed at 11 polymorphic DNA loci (restriction fragment length alleles) on chromosome 22 in tumor and normal tissue from 35 unrelated patients with meningiomas. Sixteen tumors retained the constitutional genotype along chromosome 22, while 14 tumors (40%) showed loss of one constitutional allele at all informative loci, consistent with monosomy 22 in the tumor DNA. The remaining 5 tumors (14%) showed loss of heterozygosity in the tumor DNA at one or more chromosome 22 loci and retained heterozygosity at other loci, consistent with variable terminal deletions of one chromosome 22 in the tumor DNA. The results suggest that a meningioma locus is located distal to the myoglobin locus, within 22ql2.3-qter. Multiple loci on other chromosomes also were studied, and 12 of the 19 tumors with losses of chromosome 22 alleles showed additional losses ofheterozygosity at loci on one to three other chromosomes. All tumors that retained the constitutional genotype on chromosome 22 also retained heterozygosity at all informative loci on other chromosomes analyzed, suggesting that the rearrangement of chromosome 22 is a primary event in the tumorigenesis of meningioma.
Allelic combinations at seven loci on human chromosome 17 defined by restriction fragment length polymorphisms were determined in tumor and normal tissues from 35 patients with gliomas. Loss of constitutional heterozygosity at one or more of these loci was observed in 8 of the 24 tumors displaying astrocytic differentiation and in the single primitive neuroectodermal tumor examined. (16), and here we have applied such analysis to a series of gliomas to examine clonal genotypic changes in these tumors. Our data indicate that loss of sequences on chromosome 17p, an aberration that has not been cytogenetically associated with any glioma subtype, is the only aberration we have detected in all adult malignancy grades of astrocytoma, is the most frequently observed aberration in tumors of malignancy grade II and III of this glial cell subtype, and appears to be specific to gliomas displaying solely astrocytic differentiation. Furthermore, these results indicate that the loss of chromosome 17p sequences most frequently involves mitotic recombination. As has been previously demonstrated with embryonal rhabdomyosarcoma (17), mitotic recombination mapping offers an approach toward high resolution subregional localization of loci involved in the evolution of specific tumors. The data presented here corroborate the value of this approach by revealing a region of the short arm distal to a marker in band p11.2 that attains common homozygosity for those astrocytomas losing genetic information on chromosome 17 and, thus, is inferred to harbor a locus or loci whose rearrangement is related to the development of these tumors.
The clonal loss of genetic information as revealed by the comparison of normal and tumor DNA restriction fragment length alleles has permitted the determination of the genomic positions of cancer-recessive mutations. Here we have applied this approach to the analysis of 19 central nervous system tumors that constitute four histologic groups and occur most frequently in children and young adults. The detectable loss of genetic information from cases of medulloblastoma (11 examined) indicates that among such tumors, loss occurs most frequently from the short arm of chromosome 17. For the ependymomas examined (four cases), chromosome 22 was the preferred site for detectable loss. Analysis of pilocytic astrocytomas of the cerebellum (three cases) failed to reveal genetic alterations of any type among such tumors, a finding unique to this histologic group. The single choroid plexus papilloma examined demonstrated loss of genetic information from chromosome 3. Among the 19 tumors, multiple cases of loss were observed from chromosomes 10, 11, 13, and 22, and from the short arm of chromosome 17. Therefore, with regard to the chromosomal locations of implied tumor suppressor genes, these results are consistent with those described for intracranial tumors occurring more commonly in adults of middle to advanced age.
We have previously identified and regionally localized 195 chromosome-22-specific DNA markers. We now report restriction fragment length polymorphisms detected by 9 phage markers mapped to 22q11-q12, two cosmid clones mapped to 22q12-q13 and one plasmid mapped to 22q13-qter. These markers may be useful tools for mapping disease genes such as the NF2 locus, on chromosome 22.
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