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Biomedical subjects

M E Kusak

Publications and source records attributed to M E Kusak.

At least 19 recordsLinked to original sources
PubMed2001

Mutation analysis of the p73 gene in nonastrocytic brain tumours.

Loss of heterozygosity (LOH) involving the distal chromosome 1 p36 region occurs frequently in nonastrocytic brain tumours, but the tumour suppressor gene targeted by this deletion is unknown. p73 is a novel gene that has high sequence homology and similar gene structure to the p53 gene; it has been mapped to 1 p36, and may thus represent a candidate for this tumour suppressor gene. To determine whether p73 is involved in nonastrocytic brain tumour development, we analysed 65 tumour samples including 26 oligodendrogliomas, 4 ependymomas, 5 medulloblastomas, 10 meningiomas, 2 meningeal haemangiopericytomas, 2 neurofibrosarcomas, 3 primary lymphomas, 8 schwannomas and 5 metastatic tumours to the brain, for p73 alterations. Characterization of allelic loss at 1 p36-p35 showed LOH in about 50% of cases, primarily involving oligodendroglial tumours (22 of 26 cases analysed; 85%) and meningiomas (4 of 10; 40%). PCR-SSCP and direct DNA sequencing of exons 2 to 14 of p73 revealed a missense mutation in one primary lymphoma: a G-to-A transition, with Glu291Lys change. 8 additional cases displayed no tumour-specific alterations, as 3 distinct polymorphic changes were identified: a double polymorphic change of exon 5 was found in one ependymoma and both samples derived from an oligodendroglioma, as follows: a G-to-A transition with no change in Pro 146, and a C-to-T variation with no change in Asn 204: a delG at exon 3/+12 position was identified in 4 samples corresponding to 2 oligodendrogliomas, 1 ependymoma and 1 meningioma, and a C-to-T change at exon 2/+10 position was present in a metastatic tumour. Although both LOH at 1 p36 and p73 sequence changes were evidenced in 4 cases, it is difficult to establish a causal role of the p73 variations and nonastrocytic brain tumours development.

Brain Neoplasms↗
PubMed2001

Chromosomal abnormalities in pituitary adenomas.

Cytogenetic studies were conducted on 30 pituitary adenomas, using both direct and/or short-term in vitro culture methods. An apparently normal chromosome complement was found in 14 tumors; 5 adenomas were characterized by hyperdiploid or near-triploid modal chromosome numbers. Recurrent numerical deviations were identified in 12 samples, which primarily involved gains of chromosomes 4, 7, 8, 9, 12, and 20 by gains, and losses of chromosomes 10, 14, 19, and 22. Four adenomas were shown to have structural chromosome rearrangements with no apparent recurrent pattern of involvement.

Adenoma↗
PubMed2000

High-resolution analysis of chromosome arm 1p alterations in meningioma.

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.

Brain Neoplasms↗
PubMed2000

hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas.

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.

Chromosome Deletion↗
PubMed1999

Search for mutations of the hRAD54 gene in sporadic meningiomas with deletion at 1p32.

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.

3' Untranslated Regions↗
PubMed1998

Allelic status of 1p, 14q, and 22q and NF2 gene mutations in sporadic schwannomas.

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.

Alleles↗
PubMed1998

Six novel mutations in the NF2 tumor suppressor gene.

Six novel mutations were identified in the NF2 tumor suppressor gene in a panel of meningiomas and neurinomas. Screening was performed using a combination of single-strand conformation polymorphism and heteroduplex analyses on polymerase chain reaction-amplified DNA from tumors and matched peripheral blood lymphocytes. Mutations involved exons 2, 7, 11 and 12, and corresponded to three frameshift, one nonsense, one missense and one polymorphism.

Chromosome Aberrations↗
PubMed1995

Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors.

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.

Chromosome Deletion↗
PubMed1995

Allelic status of chromosome 1 in neoplasms of the nervous system.

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.

Alleles↗
PubMed1994

Molecular analysis of chromosome 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors.

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.

Alleles↗
PubMed1994

Molecular and cytogenetic analysis of chromosome 9 deletions in 75 malignant gliomas.

A deletion mapping analysis of chromosome 9 has been performed on a series of 75 samples derived from malignant gliomas. A total of 27 tumors displayed different deletions for the loci studied (D9S1, NRASLI, D9S18, IFNA, and IFNBI). In most instances, losses involving the markers located on the short arm of chromosome 9 were observed, and only two samples were characterized by losses of the short and long arms. Either partial or complete homozygous deletions of IFN genes were observed in 15 cases, and 12 other samples showed hemizygous deletions for these genes. The results show that the 9p abnormalities are not exclusive to high-grade astrocytic tumors, as some low-grade samples (two astrocytoma grade II and six oligodendrogliomas) displayed this anomaly which, in a few instances, was the sole abnormality detected.

Chromosome Deletion↗
PubMed1994

Allelic loss at 1p is associated with tumor progression of meningiomas.

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.

Alleles↗
PubMed1994

Ascertainment of chromosome 7 gains in malignant gliomas by cytogenetic and RFLP analyses.

The incidence of gains involving chromosome 7 was determined independently using cytogenetic and molecular genetic analyses in a series of 57 malignant gliomas. Coincidental results were observed in the group of tumors in which trisomy 7 was identified on the same cells that also displayed other clonal abnormalities (i.e., losses of chromosome 10, and structural rearrangements of 1p, 9p, etc., and the presence of dmin). On the other hand, molecular detection of gain of material from this chromosome was obtained in only one of nine cases in which trisomy 7 had been identified as a solitary anomaly at the cytogenetic level. Thus, although trisomy 7 has been identified as a clonal abnormality in about 60% of gliomas analyzed cytogenetically so far, our findings suggest that the anomaly may be representative of tumor parenchyma in half of them, while in the remaining cases (mainly those in which trisomy 7 is observed at the cytogenetic level as the sole chromosomal deviation) our data agree with those suggesting that the anomaly is the result of an in vitro non-disjunction, or represent in vivo mosaicism of the non-tumoral cells.

Blotting, Southern↗
PubMed1994

Molecular analysis of genomic abnormalities in human gliomas.

A series of 57 malignant gliomas, including 27 astrocytomas grade III-IV (glioblastoma multiforme), 15 astrocytomas grade I-II, and 15 tumors with major oligodendroglial component, was examined to detect molecular abnormalities of loci at specific chromosome regions. At the cytogenetic level, these regions have been shown to be nonrandomly involved in neoplastic development of these histologic subtypes of tumor. We used a panel of 24 polymorphic DNA probes to analyze loss of heterozygosity (LOH) at loci on chromosomes 7, 9, 10, 13, 17p, and 22q. In addition, the retinoblastoma (RB1) oncosuppressor gene, the platelet-derived growth factor A (PDGFA) gene, and the epidermal growth factor receptor (EGFR) gene were analyzed directly. Loss of genetic information on the short arm of chromosome 17 was observed in both low- and high-grade astrocytomas, whereas no oligodendroglial tumor was characterized by this type of aberration. LOH for chromosome 10, mainly compatible with loss of the entire chromosome, was primarily evidenced in the more malignant forms and in isolated cases diagnosed as low-grade astrocytomas. Again, no oligodendroglial tumor displayed losses of chromosome 10. In contrast, four tumors with major oligodendroglial component showed losses involving 9p markers, primarily interferon A and B (IFNA, IFNB); this feature was also observed in two low-grade astrocytomas and in 11 high-grade tumors. Isolated cases displayed LOH for markers on chromosomes 13 and 22, whereas EGFR amplification was almost exclusively evidenced in the more malignant forms which, in most instances, also presented LOH for chromosome 10. In general, the samples with lower malignancy stage displayed a lesser grade of abnormalities, mainly restricted to losses at 17p and chromosome 10 in astrocytomas grade I-II and at 9p in oligodendrogliomas. In contrast, about 50% of the high-grade tumor samples analyzed included abnormalities at two or more loci, with a recurrent association of EGFR amplification and LOH for chromosome 10; this association was evident in 26% of the high-grade astrocytomas.

Adult↗
PubMed1993

Clonal chromosome aberrations in neurinomas.

Chromosome studies were performed after short-term in vitro culture of 39 samples from neurinomas and two samples from malignant schwannomas. Clonal abnormalities involving chromosome 22 were observed in 23 cases, as the sole chromosomal deviation in 12 of them. In 11 samples, other clonal numerical and/or structural aberrations were detected in addition to loss of chromosome 22, either in the same cells or in cells other than those having monosomy 22. Within the group of neurinomas with no involvement of chromosome 22, there were again two cytogenetically distinctive subgroups: one with an abnormal karyotype, and the second with a normal chromosome complement. Our findings confirm that monosomy 22 is a characteristic feature of this type of neoplasm, but also suggest the existence of different cytogenetic subgroups of neurinomas.

Chromosome Aberrations↗
PubMed1993

Abnormalities of chromosome 22 in human brain tumors determined by combined cytogenetic and molecular genetic approaches.

Southern blot hybridization studies were performed on a panel of 130 blood/tumor samples from brain neoplasms including all major histologic subtypes: 50 meningiomas, 18 neurinomas, 56 gliomas, and six others. To detect abnormalities involving chromosome 22, polymorphic probes were used to analyze eight loci located in this chromosome: D22S9, IGLV, D22S20, D22S32, MB, PDGF-B, D22S80, and D22S171. Loss of heterozygosity (LOH) was observed in 40 cases including monosomy, terminal, and interstitial deletions, which suggest the location of recessive tumor genes in certain chromosome 22 subregions (22q11.3-q12 in neurinomas and meningiomas, and 22q13 in malignant gliomas). Cytogenetic studies were performed in parallel on the same tumors, in most instances corroborating the presence of abnormalities for chromosome 22. Nevertheless, discrepancies between the cytogenetic and molecular findings were observed in several cases, suggesting that the use of both methodologies in combination might provide key information on the incidence and extent of the abnormalities involving chromosome 22 in human brain tumors.

Blotting, Southern↗