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The p73 gene has been mapped to 1p36.33, a chromosome region that is frequently deleted in a wide variety of neoplasms including meningiomas. The protein encoded by p73 shows structural and functional similarities to p53 and may thus represent a candidate tumor suppressor gene. To determine whether p73 is involved in the development of meningiomas, we examined 30 meningioma samples with proven 1p deletion for mutations of p73. Sequence analysis of the entire coding region of the p73 gene revealed previously reported polymorphisms in eight cases. A tumor-specific missense mutation as a result of an A-to-G transition with an Asn204Ser change was found in one meningioma that nevertheless retained the normal allele. These results suggest that if p73 plays a role in meningioma carcinogenesis, it must be in a manner different from the Knudson two-hit model.

Loss of heterozygosity (LOH) for loci on chromosome arm 1p is a relatively common event in human meningioma, and this anomaly has been proposed to be associated with the development of grade II or grade III forms (atypical and anaplastic meningiomas). Nevertheless, the limited data available do not allow the establishment of the frequency and the extent of the affected 1p regions. To determine the status of chromosome 1p in meningiomas, we have performed a comprehensive analysis of LOH on 1p in 100 meningiomas using a high density of 1p-marker loci. Allelic loss was found in 35% of tumors, most corresponding to nontypical meningiomas that also displayed losses for loci on chromosome 22. Although some tumors displayed complex rearrangements leading to distinct 1p deletions, the patterns of loss indicated two main target regions: 1p36 and 1p34-p32, which represent the most frequently involved regions, whereas 1p22 and 1p21.1-1p13 regions appeared deleted in some tumors. These results suggest that there may be several putative tumor suppressor genes on 1p, the inactivation of which may be important in the pathogenesis of meningiomas, as well as in other tumor types.

The hRAD54 protein belongs to a superfamily of DNA helicases, and mutations in genes with DNA helicase function have been found to be responsible for cancer-prone syndromes (xeroderma pigmentosum, Bloom syndrome, Werner syndrome). hRAD54 thus could be a candidate modifier gene in tumors characterized by allelic imbalance at 1p32, the chromosome region in which this gene is located. Using a panel of 38 1p and five 1q markers, we therefore performed deletion-mapping analysis on a series of 35 oligodendrogliomas, which were also studied for mutations in the hRAD54 gene. Deletions of the short arm of chromosome 1 were evidenced in 26 tumors, mostly involving 1p36-1p13; all thus displayed loss of the 1p32 region. We used PCR/SSCP to examine all 18 exons of the hRAD54 gene for mutations in 25 tumors, but the mobility shifts detected corresponded to previously identified polymorphic changes: T-to-C transition at nucleotide 2865 (with no amino acid change) and at nucleotide 3008, at the 3' untranslated region. We conclude that hRAD54 gene alterations are not required for malignant transformation of oligodendrogliomas.

The hRAD54 gene is related to a family of genes involved in DNA recombination and repair and encodes a protein with DNA helicase activity. hRAD54 has been mapped to 1p32, a region frequently involved in deletions in a variety of tumor types, including atypical and anaplastic meningiomas. To determine whether alterations of hRAD54 are a common event in meningeal tumors, by means of polymerase chain reaction-single-stranded conformation analysis we examined 29 tumor samples characterized by 1p deletions for hRAD54 mutations. Although 18 tumors displayed allelic loss at the gene region (1p32) as determined by microsatellite marker analysis, the sole coding-sequence alteration detected corresponded to a T-->C transition, with no amino-acid change. The genotype distribution was 10.34% TT, 44.8% TC, and 44.8% CC, whereas in the normal controls it was 3.77% TT, 13.2% TC, and 83.01% CC, and most meningiomas with 1 p32 deletion retained allele C. Another polymorphism due to a T-->C change was evidenced at nt 3008, in the 3' untranslated region. This change was evidenced in all cases we sequenced. These results appear to exclude the involvement of the hRAD54 gene in the pathogenesis of the nontypical meningiomas, although a detrimental effect of the hRAD54 polymorphisms cannot be ruled out.

Formation of meningiomas and their progression to malignancy may be a multi-step process, implying accumulation of genetic mutations at specific loci. To determine the relationship between early NF2 gene inactivation and the molecular mechanisms that may contribute to meningioma tumor progression, we have performed deletion mapping analysis at chromosomes 1, 14 and 22 in a series of 81 sporadic meningiomas (54 grade I (typical), 25 grade II (atypical) and two grade III (anaplastic)), which were also studied for NF2 gene mutations. Single-strand conformational polymorphism analysis was used to identify 11 mutations in five of the eight exons of the NF2 gene studied. All 11 tumors displayed loss of heterozygosity (LOH) for chromosome 22 markers; this anomaly was also detected in 33 additional tumors. Twenty-nine and 23 cases were characterized by LOH at 1p and 14q, respectively, mostly corresponding to aggressive tumors that also generally displayed LOH 22. All three alterations were detected in association in seven grade II and two grade III meningiomas, corroborating the hypothesis that the formation of aggressive meningiomas follows a multi-step tumor progression model.

Schwannomas are common benign tumours of schwann cell origin, frequently found in patients with neurofibromatosis type 2 (NF2). Inactivation of the NF2 tumour suppressor gene appears to be a molecular event responsible for the development of up to 60% of cases, but no data are available on other superimposed secondary or alternative molecular abnormalities in those schwannomas lacking NF2 gene inactivation. We analysed 23 sporadic schwannomas for mutations in the NF2 gene and for the allelic status at 1p, 14q and 22q, as alterations of these genomic regions appear to be related to tumour progression in meningiomas, another NF2-associated neoplasm. Nine samples displayed allelic losses for markers on chromosome 22, and deletions at 1p were detected in two. No case showed losses for 14q. Three tumours displayed NF2 gene mutations, at exons 2, 7 and 12. Our results confirm that inactivation of the NF2 gene is a primary event in schwannoma development, and provide data suggesting that allelic loss at 1p may contribute to the pathogenesis of a small subgroup of this histological tumour type.

By using five highly polymorphic markers, the allelic status of chromosome 1 was established in a series of 236 tumors of the nervous system, including all major histologic subtypes: gliomas, meningiomas, neurinomas, neuroblastomas, medulloblastomas, etc. Loss of alleles at 1p was observed at significant frequencies in neuroblastomas (26% of cases), meningiomas (32%), and malignant gliomas (37%) (primarily oligodendrogliomas [94%]). This anomaly was also detected in two of 23 neurinomas, two of three neurofibrosarcomas, one primary lymphoma, and two metastatic tumors of the brain. The analysis of tumors displaying partial 1p deletions suggests the existence of two distinct regions, 1p36 and 1p35-p32, in which loci nonrandomly involved in the development of neurogenic neoplasms might be located.

The molecular mechanisms underlying the genesis and progression of oligodendroglial tumors are poorly understood, since only restricted information on loss of heterozygosity from isolated cases is available. The commonest alterations appear to involve deletion of 1p and 19q, while loss of heterozygosity for 9p, chromosome 10 or epidermal growth factor receptor gene amplification have been described in single tumors. We have applied restriction fragment length polymorphism analysis to 14 loci covering chromosome 1 and 7 loci on chromosome 19 in a series of 25 tumors with an oligodendroglial component to determine precisely the participation of these suppressor genes in the genesis of tumors. Twenty-two and 19 of the 25 samples displayed LOH at 1p and 19q, respectively, and both anomalies were detected in association in 17 samples, including low- and high-grade oligodendrogliomas as well as mixed oligo-astrocytomas. Our findings suggest that inactivation of tumor suppressor genes located on 1p and 19q represent cooperative alterations occurring at early stages of oncogenic transformation of oligodendroglial neoplasms.

Alterations of the short arm of chromosome 1 are recurrently found in cytogenetic analysis of malignant gliomas, and deletions of 1p36-p32 region characterize at least the higher-grade tumors, glioblastoma multiforme. Molecular analysis of tumor-derived and normal genomic DNA from 57 cases of gliomas, using a panel of chromosome 1-specific DNA probes showed LOH in 16 tumors. Allelic losses on 1p were primarily restricted to glioblastoma multiforme (2/11) and to tumors with a major oligodendroglial component: grade II oligodendrogliomas (6/6), grade III anaplastic oligodendrogliomas (5/6) and grade II-III mixed oligo-astrocytomas (2/3). Losses for 1q markers were detected in only 1 tumor (glioblastoma multiforme). Our data suggest that anomalies of 1p primarily characterize oligodendrogliomas, whereas they are rare events in astrocytic tumors and indicate that a tumor-suppressor gene on 1p36-p32 is involved in the development of brain tumors with oligodendroglial differentiation.

Next to chromosome 22 anomalies, deletions of the short arm of chromosome 1 have previously been described as the most frequent alteration detected by cytogenetic analysis of meningiomas. To determine the incidence of these deletions, we have analyzed a series of 50 meningiomas for the loss of alleles at four chromosome 1 loci. Thirteen samples displayed LOH for the markers studied; in one instance, the results were compatible with loss of the entire chromosome 1, whereas in the other 12 samples deletions of the short arm were observed. Eleven of the meningiomas had previously been shown to have loss of alleles on chromosome 22, and 12 of them were characterized by increased tumor aggressiveness. These findings suggest that deletion of Ip (or the alteration of a locus located there) might represent a secondary, but nonrandom alteration in meningiomas, perhaps contributing to meningioma tumor progression.