Project description:Affymetrix Human Gene 2.0 ST Array profiling of 9 pairs of matched primary-metastases medulloblastoma samples. Total RNA was extracted from primary and metastases medulloblastoma samples and hybridized to Affymetrix Human Gene 2.0 ST Arrays (24-Array Plates) according to the manufacturer's instructions.
Project description:DNA methylation was generated from 11 pairs of matched primary-metastases medulloblastoma samples using the Illumina Infinium HumanMethylation450 BeadChip array Total DNA was extracted from primary and metastases medulloblastoma samples, bisulfite converted and hybridized to Illumina Infinium HumanMethylation450 BeadChip according to the manufacturer's instructions.
Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Using this dataset, assignation of medulloblastoma molecular subgroup by Illumina 450k microarray was performed for diagnostic and relapsed medulloblastoma samples to compare subgroup membership at diagnosis and relapse.
Project description:Medulloblastoma, the most common malignant pediatric brain tumour, disseminates by shedding cells into the cerebrospinal fluid, which then re-implant to cover the surface of the brain and spinal cord. Metastases are a very poor prognostic sign at presentation and are usually lethal at recurrence. Mechanisms driving dissemination have been described in the bulk primary tumour, with the underlying assumption that primary tumour and metastases are biologically similar. Here we show that in both mouse and human medulloblastoma, multiple metastases from a single animal are extremely similar, but are genetically highly divergent from the primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted sub-clone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of primary and metastatic medulloblastoma represents a major barrier to the development of effective targeted therapies.
Project description:Medulloblastoma, the most common malignant pediatric brain tumour, disseminates by shedding cells into the cerebrospinal fluid, which then re-implant to cover the surface of the brain and spinal cord. Metastases are a very poor prognostic sign at presentation and are usually lethal at recurrence. Mechanisms driving dissemination have been described in the bulk primary tumour, with the underlying assumption that primary tumour and metastases are biologically similar. Here we show that in both mouse and human medulloblastoma, multiple metastases from a single animal are extremely similar, but are genetically highly divergent from the primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted sub-clone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of primary and metastatic medulloblastoma represents a major barrier to the development of effective targeted therapies. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved human medulloblastoma tissue samples. Copy number analysis of Affymetrix SNP6 arrays was performed for 17 pediatric medulloblastoma samples. Samples comprise a series of 7 patient-matched primary/metastatic cases.
Project description:Medulloblastoma, the most common malignant pediatric brain tumour, disseminates by shedding cells into the cerebrospinal fluid, which then re-implant to cover the surface of the brain and spinal cord. Metastases are a very poor prognostic sign at presentation and are usually lethal at recurrence. Mechanisms driving dissemination have been described in the bulk primary tumour, with the underlying assumption that primary tumour and metastases are biologically similar. Here we show that in both mouse and human medulloblastoma, multiple metastases from a single animal are extremely similar, but are genetically highly divergent from the primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted sub-clone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of primary and metastatic medulloblastoma represents a major barrier to the development of effective targeted therapies. DNA methylation analysis of 15 pediatric medulloblastoma samples consisting of 6 primary-metastatic pairs and 4 normal cerebella samples profiled in Illumina Infinium HumanMethylation27 Beadchip v1.2
Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Using this dataset, assignation of medulloblastoma molecular subgroup by Illumina 450k microarray was performed for diagnostic and relapsed medulloblastoma samples to compare subgroup membership at diagnosis and relapse. We investigated the DNA methylation profiles of 18 diagnostic and 22 relapsing samples (including 15 diagnostic / relapse pairs) using the Illumina 450k methylation microarray
Project description:CTCF ChIP-seq of 39 primary samples derived from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP). Due to patient confidentiality considerations, the raw data files for this dataset have been deposited to the EGA controlled-access archive under the accession numbers EGAS00001007094 (study); EGAD00001011059 (dataset).
Project description:H3K27ac ChIP-seq of 79 primary samples derived from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP). In addition, 4 samples derived from CD34+ cord blood cells of healthy donors were included. Due to patient confidentiality considerations, the raw data files for this dataset have been deposited to the EGA controlled-access archive under the accession numbers EGAS00001007094 (study); EGAD00001011060 (dataset).