Project description:We performed a differential analysis of copy-number-alterations (CNAs) and mutations profiles by using pan-genomic array-CGH and next-generation-sequencing of 365 ‘cancer-associated’ genes, in a series of 14 pairs of matched primary breast cancer (PBC)/brain metastasis (BM) and assessed if the observed genomic alterations may be used as a druggable agent in a clinical trial.
Project description:Nectin-4 is a new therapeutic target in various carcinomas. We were interested in resistance to anti-nectin 4 ADC in breast cancer and the way to overcome it. Tumor DNA were extracted from sensitive and resistant pre-clinical models. Genomic profiles of samples were established by using array-CGH onto 4×180K CGH microarrays.
Project description:DNA microarrays were used to define the transcriptional profiles of tumor samples to compare 12 high-grade pediatric osteosarcoma tumor samples on their ALT and ATRX status.
Project description:Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous encephalopathy whose pathology is linked to an abnormal type I interferon response induced by self-derived nucleic acids. Data indicate that endogenous retroelements represent one source of interferon-stimulatory self-nucleic acid. No effective therapies are available for this disorder. In this pilot study involving patients with AGS due to mutations in TREX1, RNASEH2A, RNASEH2B or SAMHD1 three nucleoside analogue reverse transcriptase inhibitors (RTIs) were administered over 12 months. Transcription profiling was done by RNA-seq.
Project description:In some types of cancer, telomere length is maintained by the Alternative Lengthening of Telomeres (ALT) mechanism. We characterized a series of high-grade osteosarcomas from 22 non-metastatic and non-pre-treated pediatric patients. Using the presence of circular partially single-stranded extrachromosomal C-rich telomeric repeat sequences (C-Circles) as an ALT marker, we found that 16 of the 22 high-grade osteosarcomas were ALT-positive. In order to find copy number alterations associated with ALT mechanims, we used comparative genomic hybridization (CGH).
Project description:Total RNAs extracted from placental villi collected from women with (vaginal delivery) or without labor (cesarean section) at term (37-42 weeks of gestation) were hybridized to ClariomD microarrays and analyzed at the gene level to evaluate differential expression genes postlabor
Project description:We conducted a prospective monocenter clinical trial called PERMED01 to evaluate the number patients with locally advanced or metastatic cancer for whom identification of molecular alterations in tumor samples could lead to the delivery of a targeted therapy. Patients accessible to tumor biopsy were prospectively enrolled at the Paoli-Calmettes Institute in the PERMED01 study (ClinicalTrials.gov, NCT02342158). Genomic profiling of frozen tissue was established by whole-genome array comparative genomic hybridization (aCGH)
Project description:EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss of function mutations have been found in myeloproliferative neoplasms, more particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and shRNA induces MK commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and endomitosis and decreases proplatelet formation. EZH2 inhibitors similarly reduce polyploidization and proplatelet formation of JAK2V617F MK. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression for a set of genes involved in DNA replication and repair, and an upregulation of CDK inhibitors, more particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and/or CDKN2D could partially rescue the percentage of polyploid MKs. However only CDKN1A was regulated by H3K27me3 suggesting that EZH2 controls MK polyploidization through a direct regulation of CDKN1A and indirectly of CDKN2D.
Project description:The epigenetic machinery is frequently altered in acute myeloid leukemia (AML). Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22). Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration in NPM1-mutated (NPM1mut) CN-AML. H3K27me3 HIST1high group of patients
Project description:EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss of function mutations have been found in myeloproliferative neoplasms, more particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and shRNA induces MK commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and endomitosis and decreases proplatelet formation. EZH2 inhibitors similarly reduce polyploidization and proplatelet formation of JAK2V617F MK. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression for a set of genes involved in DNA replication and repair, and an upregulation of CDK inhibitors, more particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and/or CDKN2D could partially rescue the percentage of polyploid MKs. However only CDKN1A was regulated by H3K27me3 suggesting that EZH2 controls MK polyploidization through a direct regulation of CDKN1A and indirectly of CDKN2D.