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• RB1 Loss Triggers Dependence on ESRRG in Retinoblastoma

  Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed whole exomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. ESRRG is an essential mediator of hypoxic adaptation and cell survival in retinoblastoma, representing a promising new therapeutic target.

  Study phs002859

• Induced pluripotent stem cell lines (iPSC lines) produced from skin and blood cells.

  The IMBA stem cell bank, iPSC Biobank, is a collection of induced pluripotent stem cell lines (iPSC lines) produced from skin and blood cells. The iPSC Biobank is integrated into the IMBA Stem Cell Core Facility. It stores and provides high-quality reference control panels of iPSC clones as a tool to the research community. The resource is available to all scientists and commercial institutions. The ethical guidelines of the iPSC Biobank are always based on prevailing laws and internal regulations.

  Study EGAS00001006262

• The Genetic Basis of Hypodiploid ALL

  The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

  Study phs000341

• Spatio-temporal evolution of the primary glioblastoma genome

  Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of 38 GBM patients with the initial and recurrent tumor specimens for each individual. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk of TMZ-induced hypermutation for these patients under the standard regimen.

  Study EGAS00001001041

• PRDM9 loss of function follow up from Born-in-Bradford Autozygosity sequencing

  In the autozygosity exome sequencing of Born-in-Bradford samples of Pakistani origin there is a mother who is homozygous for an apparent truncating stop codon in PRDM9, the gene responsible for localising recombination during meiosis. We plan to deep sequence mother and child with X10, and physically phase the mother with PacBio sequencing. We will use this data to identify recombination locations, and test whether these are consistent with the known fine scale recombination map. Data Access is controlled by the Wellcome Trust Sanger Institute DAC and the Born In Bradford Executive Group.

  Dataset EGAD00001001686

• Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors

  Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved cancer treatment. In this study, we use patient derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate invivo efficacy of methotrexate in an MRT PDX mouse model. Our study revealsnucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

  Study EGAS00001007877

• Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

  Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

  Study EGAS00001003750

• Physiological and genetic adaptations to diving in Sea Nomads

  Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people (“Sea Nomads”) of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong natural selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other natural diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance.

  Study EGAS00001002823

• Initial leukemic epigenomic state determines hypomethylating agent response

  Hypomethylating agents (HMAs) are a mainstay of therapy for myeloid cancers, but genetic biomarkers do not predict who will respond to treatment. Using a variety of single-cell sequencing approaches to define the epigenomic state of responder and nonresponder leukemic cells, we aim to demonstrate that leukemic stem cells (LSC) exist in at least two different epigenomic states: a hematopoietic stem cell (HSC)-or multipotent progenitor (MPP)-like state that is sensitive to HMAs, independent of genetic mutations, or a lymphoid-primed MPP (LMPP)-like nonresponder state. Additionally, we aim to demonstrate that hypomethylation and chromatin accessibility at ZNF143- and CTCF-binding sites result in activation of HOXB4, which defines the HSC/MPP-like state and HMA-sensitivity. Our study aims to provide evidence that the epigenomic state of the LSC is a major determinant of response to HMAs, and demonstrates that a routine clinical assay can identify patients who will respond.

  Study EGAS50000000936

• Suspected Lynch syndrome dataset

  This dataset comprises a genomic and a phenotypic excel sheet displaying 137 cases classified as suspected Lynch syndrome. Included are genotypic data such as tumour mutational burden, tumour mutational signatures and germline/somatic variant calls for each colorectal, endometrial or sebaceous skin tumour screened. Genomic data is derived from targeted multigene panel sequencing including ~300 hereditary cancer genes.

  Dataset EGAD50000000031