Biomedical subjects

Micheline Giphart-Gassler

Publications and source records attributed to Micheline Giphart-Gassler.

5 recordsLinked to original sources

PubMed2006

Lack of genetic and epigenetic changes in meningiomas without NF2 loss.

Approximately 60% of sporadic meningiomas are caused by inactivation of the NF2 tumour suppressor gene. The causative gene for the remaining meningiomas is unknown. Previous studies have shown that these tumours have no recurrent karyotypic abnormalities. They differ from their NF2-related counterparts in that they are more often of the meningothelial subtype and are located preferentially in the anterior skull base. To gain more insight into the aetiology of these tumours, we studied genetic and epigenetic alterations in 25 meningiomas without NF2 involvement. We first established a genome-wide allelotype using 3 microsatellite markers per chromosome arm. Loss of heterozygosity (LOH) was detected at a low frequency and no indication for the location of putative tumour suppressor genes could be established. We next screened the subtelomeric regions by using 2-3 polymorphic markers close to each telomere. Again no evidence for LOH of a particular chromosome arm was obtained, and no LOH was found in the genomic regions containing the NF2-related ERM family members ezrin and radixin, DAL-1, protein 4.1R, and TSLC1. Mutations in the X-chromosome based family member, moesin, were analysed by SSCP and were not detected. Microsatellite instability was studied using 6 commonly used markers but none of these was altered in any meningioma. Methylation was detected in 5 of 16 genes (NF2, p14(ARF), CDH1, BRCA1, RB1) previously shown to be silenced in a variety of tumour types. However, methylation percentages for these genes were generally higher in a group of NF2-related meningiomas, with the exception of the BRCA1 gene. The NF2 gene was methylated in only 1 of 21 tumours. In conclusion, meningiomas with an intact NF2 gene have a normal karyotype and no obvious genetic or epigenetic aberrations, suggesting that the gene(s) involved in the pathogenesis of these tumours are altered by smaller events than can be detected with the techniques used in our study.

Adult↗

PubMed2006

Analysis of gene expression using gene sets discriminates cancer patients with and without late radiation toxicity.

BACKGROUND: Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%-10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity. METHODS AND FINDINGS: Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization.X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier. CONCLUSIONS: Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.

Aged↗

PubMed2005

Dissecting systems-wide data using mixture models: application to identify affected cellular processes.

BACKGROUND: Functional analysis of data from genome-scale experiments, such as microarrays, requires an extensive selection of differentially expressed genes. Under many conditions, the proportion of differentially expressed genes is considerable, making the selection criteria a balance between the inclusion of false positives and the exclusion of false negatives. RESULTS: We developed an analytical method to determine a p-value threshold from a microarray experiment that is dependent on the quality and design of the data set. To this aim, populations of p-values are modeled as mathematical functions in which the parameters to describe these functions are estimated in an unsupervised manner. The strength of the method is exemplified by its application to a published gene expression data set of sporadic and familial breast tumors with BRCA1 or BRCA2 mutations. CONCLUSION: We present an objective and unsupervised way to set thresholds adapted to the quality and design of the experiment. The resulting mathematical description of the data sets of genome-scale experiments enables a probabilistic approach in systems biology.

Breast Neoplasms↗

PubMed2003

Identification of RUNX1/AML1 as a classical tumor suppressor gene.

Based on our previous results indicating the presence of a tumor suppressor gene (TSG), chromosome 21 was analysed for loss of heterozygosity (LOH) in 18 patients with acute myeloid leukemia (17, AML-M0; one, AML-M1). Allelotyping at polymorphic loci was performed on purified material, allowing unequivocal detection of allelic loss and homozygous deletions. Six AML-M0 patients shared a common region of LOH harboring a single gene: RUNX1 (AML1), the most frequent site of translocations in acute leukemia and a well-known fusion oncogene. Fluorescence in situ hybridization allowed the identification of deletions with breakpoints within RUNX1 in two patients as the cause of LOH. In the four others the LOH pattern and the presence of two karyotypically normal chromosomes 21 were in line with mitotic recombination. Further molecular and cytogenetic analyses showed that this caused homozygosity of primary RUNX1 mutations: two point mutations, a partial deletion and, most significantly, a complete deletion of RUNX1. These findings identify RUNX1 as a classical TSG: both alleles are mutated or absent in cancer cells from four of the 17 AML-M0 patients examined. In contrast to AML-M0, the AML-M1 patient was trisomic for chromosome 21 and has two mutated and one normal RUNX1 allele, suggesting that the order of mutagenic events leading to leukemia may influence the predominant tumor type.

Acute Disease↗

PubMed2002

Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system.

Loss of heterozygosity (LOH) is a major mechanism for inactivation of tumor-suppressor genes and has been observed in various solid tumors and lymphomas. The human leukocyte antigen (HLA) region is located at chromosome band 6p21.3, and loss or alteration of this region may provide tumor cells with a mechanism to escape from the immune system. We previously identified small homozygous deletions within the HLA class II region in many of the diffuse large B-cell lymphomas (DLCLs) of the central nervous system (CNS) and the testis. In the present study, we focused on the mechanism leading to LOH in the HLA region. Twenty microsatellite markers, of which 12 were specific for HLA, were applied on 11 extranodal DLCLs of the CNS and 28 of the testis. Additionally, fluorescence in situ hybridization with seven HLA-specific probes and a centromere 6-specific probe was performed on 20 cases to study the mechanism of LOH. In contrast to previously published data on spontaneously mutated lymphoblastoid cell lines, intrachromosomal hemizygous deletion, not mitotic recombination, was the major cause of LOH of the HLA region in these lymphomas. However, opposed to data in colorectal cancer, these deletions were rarely (one of nine cases) associated with an interchromosomal rearrangement such as a translocation.

Alleles↗