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• GEenetic landscape of hypodiploid acute lymphoblastic leukemia

  Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive leukemia characterized by aneuploidy and poor outcome. The genetic basis of hypodiploid ALL is unknown. Here, using complementary genome-wide profiling approaches, we show that hypodiploid ALL comprises two subtypes that differ in the severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24-31 chromosomes frequently harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL cases with 32-39 chromosomes are characterized by TP53 alterations, almost half of which are present in non-tumor cells, and have alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras and PI3K signaling pathways, and are sensitive to PI3K inhibition, indicating that these drugs should be explored as a new therapeutic strategy for this frequently lethal form of leukemia.

  Study EGAS00001000380

• DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

  To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

  Study EGAS00001002224

• Jeju Genome Project DAC

  This Data Access Committee (DAC) evaluates and manages access requests for large-scale genomic and phenotypic datasets generated as part of the Jeju Genome Project (JGP). The committee's mission is to facilitate responsible data sharing to advance precision medicine and population genetics. The DAC ensures that data access is granted only to bona fide researchers who agree to the terms of the Data Access Agreement (DAA) and whose proposed research is strictly consistent with the informed consent provided by the participants and the ethical guidelines of the project.

  Dac EGAC50000000938

• An Advanced Molecular Medicine Case Report of a Rare Human Tumor Using Genomics, Pathomics, and Radiomics

  The associated data of this study is derived from a single female patient with pulmonary sclerosing pneumocytoma (PSP). The aim of this study is to provide the most comprehensive, multi-modality sequencing study of a single case of PSP to-date. To this end, the following sequencing experiments were performed: i) RNA-Seq of the primary tumor and adjacent normal tissues (6 replicates for each tissue type), which was intended to analyze RNA-Seq fusions, gene expression, expression mutations, ii) low-pass DNA whole genome sequencing (WGS) from primary tumor tissue and germline, which was intended to analyze copy number aberrations, and iii) DNA targeted panel sequencing of lung cancer associated genes, using primary tumor tissue and germline from white blood cells, which was intended to analyze somatic mutations. Principal findings: i) the PSP hallmark mutation AKT1 (p.E17K) was detected within both the DNA and RNA, and ii) the TP53 signaling pathway was found to be statistically significant by three different pathway analysis tools of analyzing gene expression and pathway ramifications. Among proteins within the TP53 signaling pathway, the p53 inhibitor encoded by MDM2 was found to be overexpressed (by differential gene expression analysis). The original sequencing data (i.e., FastQ files) from each of the aforementioned samples will be accessible through dbGaP.

  Study phs003154

• Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant

  Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

  Dataset EGAD50000000359

• Longread sequencing of selected 12q-amplified osteosarcomas

  Longread sequencing of selected 12q-amplified osteosarcomas for verification of SV data. This was carried out in order to verify findings from mate-pair sequencing regarding the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification.

  Study EGAS50000000495

• Ensemble learning for classifying single-cell data and projection across reference atlases

  Single-cell data are being generated at an accelerating pace.How best to project data across single-cell atlases is an open problem. We developed a boosted learner that overcomes the greatest challenge with status quo classifiers: low sensitivity, especially when dealing with rare cell types.

  Study EGAS00001004283

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• Molecular Attributes Underlying Central Nervous System and Systemic Relapse in Diffuse Large B-cell Lymphoma

  Central nervous system (CNS) relapse in diffuse large B-cell lymphoma remains a significant conundrum. While clinical risk scores and biomarkers allow the identification of patients with higher risk of CNS relapse, their predictive ability is low. Herein, we report findings from a comprehensive study examining gene expression changes, mutations and clonal evolution. Firstly, considering diagnostic samples from patients with CNS relapse, systemic relapse or no relapse, we found a striking enrichment of gene expression changes reflecting protein biosynthesis in patients who experienced CNS or systemic relapse. Furthermore, diagnostic specimens of relapsing cases were characterized by low immune infiltrates. The most discriminative gene feature in our analysis was SLAMF1, high expression of which was associated with favourable outcomes. Next, we assessed whether specific gene mutations were associated with subsequent CNS or systemic relapse. Activated B-cell-like genes such as PIM1, CD79B and PRDM1 were more frequently mutated in cases with CNS relapse, whereas TP53, BCL2 and FOXO1 mutations were associated with systemic relapse. Lastly, we performed tumor evolution analysis in five patients, identifying significant clonal divergence that accompanied CNS relapse. In summary, we identified both common biology underlying both CNS and systemic relapse, independent of cell-of-origin (COO), and specific COO-enriched gene mutations that conferred a higher risk of either CNS or systemic relapse. Moreover, we identified a pattern of clonal evolution that can explain difficulties in both predicting and treating CNS relapse.

  Study EGAS00001004057

• Epidemiological study comparing rates and risk factors for dementia in African Americans in Indianapolis and Yoruba living in Ibadan, Nigeria

  In 1991 collaboration between researchers at Indiana University School of Medicine and the University of Ibadan, Ibadan, Nigeria established the Indianapolis-Ibadan Dementia Project. It is a longitudinal, prospective population-based comparative epidemiological study of the prevalence and incidence rates and risk factors of Alzheimer's disease and other age associated dementias. The project compares samples of community-dwelling elderly (age > 70 years) African Americans living in Indianapolis to Yoruba living in Ibadan, Nigeria, employing the same research design, methods, and investigators. It initially reported significantly lower prevalence rates of disorders in the Yoruba compared to the African Americans. In subsequent waves of the study (1994-1995, 1997-1998) incidence rates, rates of newly diagnosed cases, were also found to be significantly lower in the Yoruba. In genetic studies, the frequency of the APOE 4 allele was about the same in the two groups. APOE 4 was a significant risk factor for Alzheimer's disease and dementia in the Americans, while no association was found for the Yoruba. The APOE 2 allele appears to be protective in the Americans, but not the Yoruba. A constellation of factors often associated with vascular risk including a history of hypertension, diabetes, and high cholesterol levels is less common in the Yoruba than in the American group. An interaction was observed between cholesterol, APOE genotype and Alzheimer's disease in both study groups. In 2001-2002 survivors of the original cohort were once again evaluated (N~800 in each site) and 2,000 additional individuals age 70 years and older were enrolled in each site. Blood samples were collected from approximately 1,500 study participants in each site for genetic studies and analysis of biochemical risk factors for vascular disease. Subsequent waves of field work were conducted in 2004, 2007, 2009, and 2011. This fieldwork followed the classic two-stage study design. The study design involves an in-home screening interview with the study participant, which includes a cognitive assessment, medical history and current medications, brief neurological examination, height and weight, blood pressure measurement and assessment of social involvement. There is also a screening interview with a close relative of the study participant to assess activities of daily living, personality change, and medical history of the study participant. On the basis of the screening interview a sample of study participants (N~500 in each site) is selected for a full clinical diagnostic dementia work up which includes a neurological test battery, extensive interview with a family member and examination by a clinician. Diagnoses are made in a consensus diagnosis conference using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III R) and International Classification of Diseases 10th Revision (ICD-10) for dementia. The criteria of the National Institute for Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association were used to diagnose possible and probable Alzheimer's disease. The focus of the study is risk factors for dementia and Alzheimer's disease, but also of particular importance is the question of mild cognitive impairment. This refers to the condition of having some decline in cognition but the decline is not sufficient to meet the criteria for dementia. We have studied this over the course of this project. In follow up studies of individuals who have this diagnosis about one third of them are better at follow up, about a third are about the same, and about a third decline more to meet the criteria for dementia. This is a very important issue for researchers because the ultimate goal of the research is to figure out how to identify the individuals who will definitely progress to dementia. If there are clear identifiers, it would be possible to make interventions, while individuals still function well, and possibly prevent the development of dementia altogether or delay the onset significantly. This is crucial because at the moment individuals usually do not enter into the medical care system until the dementia symptoms are quite severe, and the pathological damage to the brain cannot be undone.

  Study phs000378