Identification et impacts des anomalies genetiques dans la genese, l'evolution clinique et le traitement des gliomes.

摘要

Human gliomas represent the most common primary brain tumours in adults. According to World Health Organization classification, gliomas are divided into astrocytomas with four grades (I, II, III, and IV), oligodendrogliomas with two grades (II and III), and oligoastrocytomas with two grades (II and III) based on the tumor cell phenotype. Pathological classification remains controversial due to the lack of specific immunohistochemical biomarker to recognize gliomas. Also, due to their natural propriety to infiltrate the normal parenchyma and to migrate far from the first location, total surgical resection remains often impossible then adjuvant treatment is needed. The established therapies for gliomas include surgery, radiotherapy and chemotherapy. Despite this arsenal of therapies, median survival of the most malignant grade glioblastoma is approximately 15 months. This is why the attempts to better understand the molecular biology of gliomas in the aim to define new molecular targets is a holy grail. Using conventional and molecular cytogenetic approaches and molecular genetic methods, we have investigated patients bearing gliomas and followed at CHUS. Our results display that the codeletion 1p/19q (1p-/19-) is not only a prognostic and predictive biomarker of oligodendrogliomas but also a diagnostic tool of this tumor. Our study has allowed us to build a glioma-bank containing around 150 samples of patients, which we continued to populate. We have also defined the cut-off positivity of FISH on touch preparation slides, which is 20%. In addition, we have developed a new, fast and reliable method to retrieve the 1p-/19q- in all samples 24 hours after sampling. This method was transferred to the clinical lab. Furthermore, we have successfully cultured the brain tumor samples and analyzed their caryotypes. This has permitted us to discover a new alternative translocation, which is responsable of 1p deletion in one oligoastrocytoma case. Since glioblastoma is characterized by genomic instability, and telomere disruption is a main cause of genomic instability, we investigated the nuclear telomere architecture in this type of tumour. We found that nuclear telomeric architecture could be a biomarker of glioblastoma since it can subdivide glioblastoma patients in three categories with significantly different outcomes and time to progression. We used high-throughput methods (one manual and one semi-automatic) to characterize the nuclear telomeric architecture in glioblastoma. The semi-automatic method can be transfer to the clinical lab since it can deliver the results nine hours after sampling. Then, this approach is usable to monitor this tumor and to evaluate the impact of different treatment options. We need to search the putative tumor suppressor genes on chromosomes 1 and 19. Furthermore, trying to understand the molecular basis of nuclear telomeric architecture will bring up new molecular target therapies.;Keywords : Gliomas, chromosomal abnormalities, genetic instability, genomic instability, 1p/19q, telomeres, nuclear architecture, EGFR.