12405 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)

  Purpose: Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Experimental Design: Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Results: In the preclinical match study, we identified one specific single agent response to LY3023414 in an osteosarcoma model with a TSC2 variant of unknown significance. Combinations of nano-liposomal irinotecan were effective in treating both Ewing sarcoma and rhabdomyosarcoma xenografts. Conclusion: Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.

  Study EGAS00001008011

• Whole exome sequencing data for paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours.

  Introduction: Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic relationship. Methodology: This study investigates the extent of relatedness using whole exome sequencing, which was performed on paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours in a cohort with detailed clinicopathological annotation. Four whole exome sequencing-derived parameters (mutation, mutational burden, mutational signatures and mutant allele tumour heterogeneity scores) were used to develop a novel unsupervised model for the assessment of genomic similarity to infer genomic relatedness of paired tumours. Results: This novel model demonstrated genomic relatedness across all four parameters in all tumour pairs. Mutations in PTEN, ARID1A, CTNNB1, KMT2D and PIK3CA occurred most frequently and 24 of 27 (89 %) tumour pairs shared identical mutations in at least one of these genes, with all pairs sharing mutations in a number of other genes. Ovarian endometriosis, CTNNB1 exon 3 mutation, and progression and death from disease were present across the similarity ranking. Mismatch repair deficiency was associated with less genomically similar pairs. Discussion: Although there was diversity across the cohort, the presence of genomic similarity in all paired tumours supports the hypothesis that concurrent non-serous endometrial and ovarian carcinomas are genomically related and may have arisen from a common origin. Keywords: Co-existing; Concurrent; Endometrial carcinoma; Genomics; Mutation; Ovarian carcinoma; Paired tumours; Tumour mutational burden.

  Study EGAS00001008259

• Rare germline variants in patients with personal and family history of colorectal cancer

  A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to find novel high/moderate penetrance CRC susceptibility genes, we performed whole-exome sequencing on germline blood samples of seven familial cases from Poland with a double primary CRC.

  Dataset EGAD50000000861

• Novel genome editing strategies to uncover genotype-phenotype correlations in Polycystic Kidney Disease: a proof-of-concept

  Bulk RNA-seq of genome-edited HEK293T cell lines engineered to model specific PKD1 variants. This dataset enables the exploration of genotype-phenotype correlations in Polycystic Kidney Disease (PKD)

  Study EGAS50000001188

• ExomeSeq Neoantigen Immunogenicity Landscapes

  Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet the fundamental physiochemical characteristics of neoantigens and how neoantigen immunogenicity shapes treatment response remains poorly understood. To help address these questions, a prospective clinical trial of NSCLC patients treated with nivolumab was conducted. We assessed genomic alterations in tumors from 58 patients and performed large-scale neoepitope immunogenicity analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenically recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic neoantigen harboring clones compared to non-immunogenic clones. Using this large collection of neoantigens, we identified position specific amino acid features related to immunogenicity, which we used to develop and validate an immunogenicity score. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the neoantigen landscapes underlying nivolumab’s mechanism of action.

  Study EGAS00001007508

• RNASeq Neoantigen Immunogenicity Landscape

  Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet the fundamental physiochemical characteristics of neoantigens and how neoantigen immunogenicity shapes treatment response remains poorly understood. To help address these questions, a prospective clinical trial of NSCLC patients treated with nivolumab was conducted. We assessed genomic alterations in tumors from 58 patients and performed large-scale neoepitope immunogenicity analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenically recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic neoantigen harboring clones compared to non-immunogenic clones. Using this large collection of neoantigens, we identified position specific amino acid features related to immunogenicity, which we used to develop and validate an immunogenicity score. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the neoantigen landscapes underlying nivolumab’s mechanism of action.

  Study EGAS00001007509

• Screening Cases of Isolated Dystonia for Variants in CIZ1

  Recently, we have identified that variants in CIZ1 gene is associated with dystonia. To identify the prevalence of CIZ1 mutations in dystonia population, we use High resolution melting (HRM) to examine all the coding sequence in 3976 subjects with primary dystonia as well as 1819 subjects of normal controls. Indels in Q rich region of exon 2 in CIZ1 were identified in 21 subjects with dystonia but only 3 controls (P<0.05). Other single nucleotide change variants were also found in some of the patients which include a novel missense mutation (c.787A>G, p.R263G) found in a female patient with apparently familial dystonia. We confirmed that mutations in CIZ1 could be associated with dystonia but in rare cases.

  Study phs001455

• Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

  In a genome-wide genetic study of early progression to active tuberculosis (TB), we genotyped 4,002 active TB cases and their household contacts in Lima, Peru. We first established TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases (h2g=0.212). We identified a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 x 10-8). With in silico and in vitro analyses we identified genetic variant rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

  Study phs002025

• IKZF5 RNAseq samples for platelets, neutrophils, monocytes and CD4+ T-cells.

  To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

  Dataset EGAD00001005107

• The genomic landscape of pediatric acute lymphoblastic leukemia

  Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and arises from B- or T-lineage lymphocyte precursors. ALL comprises dozens of subtypes, and genomic analyses have largely been performed within these subtypes. Here we analyze pediatric ALL genomes across all subtypes, including 768 whole genomes, 1,729 exomes, and 1,889 transcriptomes in 2,754 patients. Most ALL subtypes harbor 4 or more driver alterations per sample, similar to adult cancers, despite low mutation burdens. Hyperdiploid B-ALL copy gains are likely acquired early and synchronously, with copy gains occurring before ultraviolet-induced mutations. By contrast, ultraviolet-induced mutations precede copy gains in iAMP21 B-ALL. Overall, we identified 378 putative ALL driver genes. Most driver alterations vary in prevalence across ALL subtypes, with B-ALL enriched for Ras and B-lineage-related alterations, and T-ALL enriched for PI3K, JAK, and cell cycle alterations. Most B-ALL (54.3%) and T-ALL (51.2%) samples bear at least one rare driver gene alteration (present in less than 2% of samples), including 30 putative novel cancer driver genes associated with ubiquitination, SUMOylation, non-coding, and other functions. Known or novel alterations associated with poor outcomes in specific subtypes include TBL1XR1 alterations in ETV6-RUNX1 patients, CREBBP in Ph-like-CRLF2, SETD2 in hyperdiploid, and PTEN in TAL1 patients. Intriguingly, DUX4 and KMT2A subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of ALL etiology and outcomes, and facilitate ALL model development.

  Study EGAS00001005250

• Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

  Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

  Study EGAS00001004063

• Development of Novel Chondrosarcoma Organoid Models for Drug Discovery

  Chondrosarcoma is a rare and aggressive malignant bone tumor characterized by resistance to conventional chemotherapy and radiotherapy. Its pathogenesis remains poorly understood, although recurrent mutations such as IDH1 have been implicated in tumor development. We treated patients with chondrosarcoma at the Osaka International Cancer Institute and established two organoid cultures from resected tumor specimens using a modified air-liquid interface method. After serial passaging, the organoids were successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoids retained key histological features and genetic characteristics of the original tumors. These organoid models provide a novel and reliable platform for studying the biology of chondrosarcoma and may facilitate the development of effective therapeutic strategies for this treatment-resistant tumor.

  Study JGAS000834

• cfDNA in Hereditary And High-Risk Malignancies (CHARM)

  Our goal is to improve early cancer detection by developing a blood test to predict cancer development in carriers using circulating DNA. As carriers develop cancer, they may have pre-cancerous cells which release this DNA into the blood (cell-free DNA; cfDNA), which can be detected with novel genetic technologies. We propose to use three complementary cfDNA assays:shallow whole genome sequencing (sWGS), Liquid-Biopsy Sequencing (LB-Seq) and Cell-free Methylated DNA Immunoprecipitation and High-throughput Sequencing (cfMeDip-Seq) for early cancer detection.

  Study EGAS00001006539

• Decoding Human Heart Morphogenesis through Single-cell Multi-modal Analyses

  The heart, which is the first organ to develop, is highly dependent on its form to function. However, how diverse cardiac cell types spatially coordinate to create complex morphological structures critical for heart function remains to be elucidated. Here, we show that integration of single cell RNA-sequencing with high-resolution multiplexed error-robust fluorescent in situ hybridization (MERFISH) not only resolves the identity of cardiac cell types developing the human heart but also provides a spatial mapping of individual cells that enables illumination of their organization into cellular communities forming distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, supporting their specialization according to cellular ecosystem and anatomic region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities revealed signaling pathways orchestrating the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. In vivo conditional genetic mouse models and in vitro human pluripotent stem cell studies confirmed an intricate multicellular PLXN-SEMA crosstalk among specific ventricular cardiomyocyte, fibroblast and endothelial cell subpopulations that directs the compaction of the ventricular wall layers. Thus, these detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodeling the human heart offer new insights into structural heart diseases as well as engineering complex multi-cellular tissues for human heart repair. Reprinted from Farah et al. (In press), with permission from Nature.

  Study phs002031

• Monocyte and macrophage lipid accumulation results in downregulated type-I interferon responses

  Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

  Study EGAS00001005955

• Ashkenazi Jewish Leukoencephalopathy

  Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities in the central nervous system (CNS). Patients affected with gLEs have brain white matter defects that can be seen in MRI and exhibit variable neurologic phenotypes including motor impairment, hypotonia, pyramidal dysfunction, dystonia and/or dyskinesias, ataxia, seizures, cortical blindness, optic atrophy, and impaired cognitive development. The exact causes in half of gLEs are unknown. We studied three unrelated families affected with an undiagnosed gLE and discovered a homozygous germline mutation c.2536T>G in VPS11 by whole exome sequencing, a gene involved in membrane trafficking and fusion of the lysosomes and endosomes, as a novel cause of a new gLE syndrome.

  Study EGAS00001001767

• TIRE-seq: an Integrated Sample Extraction and Transcriptomics Workflow for High Throughput Perturbation Studies

  TIRE-seq is a novel RNA sequencing method that integrates mRNA purification directly into library preparation, eliminating separate RNA extraction. The technique demonstrated utility across three biological applications, including capturing transcriptional changes in human T cells, identifying genes driving murine dendritic cell differentiation, and analyzing the dose-response effects of temozolomide on patient-derived neurospheres. With its simplified approach and high sequencing efficiency, TIRE-seq offers a cost-effective solution for large-scale gene expression studies.

  Study EGAS50000000867

• Observational studies using advanced analytical techniques to understand the biological functions of kidney component cells

  The purpose of this study is to establish a foundation for understanding the functions of kidney component cells and the biology of renal disease. Single cell and spatial transcriptome analyses of human kidney component cells will be performed to analyze the gene expression profiles of those cells and explore their relationship between the gene expression profiles and clinical parameters. The research foundation established here is worthwhile for understanding disease mechanisms in the kidney or discovering novel therapeutic drugs for renal disease.

  Study JGAS000736

• An Ultrasensitive Method for Detection of Cell-Free RNA

  Our study describes the development of a novel method for cell free RNA (cfRNA) analysis called RARE-Seq (Random priming & Affinity capture of cell-free RNA fragments for Enrichment analysis by Sequencing). We find RARE-Seq improves the limit of detection for tumor-naïve cancer detection while maintaining high specificity. We explore the potential utility of RARE-Seq in diverse clinical applications, including non-invasive ctRNA genotyping, treatment resistance monitoring, and molecular characterization of non-malignant conditions.

  Study phs004091

• Spatial Profiling of Patient-Matched HER2 Positive Gastric Cancer Reveals Resistance Mechanisms to Trastuzumab and Trastuzumab Deruxtecan Sequencing

  HER2-positive gastric cancer (HER2+ GC) exhibits significant intra-tumoral heterogeneity and frequent development of resistance to HER2-targeted therapies. This study aimed to characterize the spatial tumor microenvironment (TME) and identify mechanisms of resistance to HER2 blockade including trastuzumab and trastuzumab deruxtecan (T-DXd) in HER2+ GC, with the goal of informing novel therapeutic strategies. We performed spatial transcriptomics on pre- and post-treatment samples from patients with HER2+ metastatic GC who received trastuzumab-based therapy.

  Study EGAS50000000636

• ERDERA Diagnostic Research Workstream - WES reanalysis (distributed approach)

  The ERDERA Diagnostic Research Workstream – WES reanalysis (distributed approach) aims to improve diagnostic yield by systematically reanalyzing existing whole exome sequencing (WES) data from rare disease cases. The goal is to apply updated bioinformatics pipelines, novel variant interpretation tools, and the latest reference databases to detect clinically relevant variants that may have been missed in earlier analyses. By using a distributed approach across multiple expert groups, the project fosters collaborative interpretation and knowledge sharing to enhance diagnostic outcomes for patients.

  Study EGAS50000001514

• WGS of breast cancer diagnosed during pregnancy and matched control

  The aim of this study was to compare the mutational landscape of breast cancer diagnosed during pregnancy (BCP) and breast cancer from age/stage non-pregnant patients (controls). We present whole genome sequencing data (Illumina HiSeq X ten platform) of tumor and matched normal tissues from 35 BCP patients and 20 controls. This work provides important novel biological insights and a unique resource to study the biology of breast cancer in young women and how pregnancy could modulate tumor biology.

  Study EGAS00001002685

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML___part2

  Genomic libraries will be generated from total genomic DNA derived from 4000 samples with Acute Myeloid Leukaemia. Libraries will be enriched for a selected panel of genes using a bespoke pulldown protocol. 64 Samples will be individually barcoded and subjected to up to one lanes of Illumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the characterisation of known gene mutations in cancer as well as the validation of potentially novel variants identified by prior exome sequencing.

  Study EGAS00001000570

• The University of Hong Kong Gastric Cancer Organoids RHO Signaling Study

  Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix, or both, to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA, and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to 3 public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to re-sensitization to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype, and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

  Study EGAS00001006252

• Analysis of Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

  High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.

  Study phs000413