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• Extreme phenotypes define epigenetic and metabolic signatures in cardiovascular diseases.

  Improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.

  Study EGAS00001003780

• Nicotine Addiction Genetics and Correlates

  Ascertainment: Families were ascertained through panels of adult Australian twins, and a sample of spouses of Australian twins. Families with at least one offspring who was identified as a current or former smoker in an earlier survey. Screening telephone interviews were conducted with index cases to provide confirmation of a history of heavy cigarette smoking, to obtain confirmation of a history of heavy cigarette smoking, and to obtain additional information on the history of cigarette use and the survival status of other family members, and their full siblings and parents. Index cases were the affected spouse of a twin, or the affected twin from pairs discordant for a history of heavy smoking, or a randomly chosen twin from pairs where both have a history of regular smoking (i.e., has smoked at least 100 cigarettes lifetime), and at least one live biological parent to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent. If permission was granted by the index case, eligible family members were contacted and invited to provide a blood sample and to complete a telephone diagnostic interview. In families with just one available biological parent, and additional unaffected sibling who had never smoked on a regular basis (i.e., has smoked fewer than 100 cigarette lifetime, but has experimented with cigarettes once or twice) was included (when available) to help compensate for the loss of information due to missing parental phenotypes. (Target N=400 Australian families with approximately 600 ASPs; and 600 TDT trios comprised of a nicotine dependent index case and both biological parents). Diagnostic Assessment: The telephone diagnostic interview assessed DSM-IV and modified DSM-IIIR diagnoses (i.e., without time clustering) for nicotine dependence, alcohol and other drug dependence and abuse, major depression, and childhood conduct disorder. Most diagnostic assessments were based on the SSAGA/SSAGA-II, developed for the multi-site gene-mapping alcoholism study (the Collaborative Study on the Genetics of Alcohol. An exception was the tobacco section, which was developed directly from the CIDI and DIS (as the original SSAGA did not include a diagnostic section on nicotine dependence). In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001299

• Developing Targeted Therapy for Patients with Multiple Myeloma and Gain or Amplification of Chr1q (1q+)

  Multiple myeloma (MM) frequently presents with gain or amplification of chr1q (1q+), which is associated with inferior response to treatment and poor outcomes. To develop targeted therapy for MM with 1q+, we leveraged external and in-house dependency screens and drug screens, along with single-cell sequencing of patient tumors with subclonal 1q+. We demonstrated that MM with 1q+ exhibits higher sensitivity to MCL1 and PI3K inhibitors, which may be synergistic and act through established and novel mechanisms. Two human MM cell lines with 1q+, KMS12BM and KMS11, were profiled with either single-cell RNA-sequencing (scRNA-seq) alone (KMS12BM, KMS11) or both scRNA-seq and whole-genome sequencing (WGS; KMS12BM) to understand the factors that determine response to MCL1 and PI3K inhibitors and how these inhibitors work.

  Study phs003886

• CRISPR-Mediated ASD Gene Knockout Reduces Neuronal Activity

  Autism Spectrum Disorder is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of 10 ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNAseq revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory post-synaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.

  Study phs001816

• Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

  Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  Study EGAS00001003620

• Spatial genomic heterogeneity in multiple myeloma revealed by multi- region sequencing

  The bone-marrow (BM) containing skeletal system is the reservoir of Multiple Myeloma (MM), the malignant counterpart of antibody-secreting plasma cells. To gain insight into its spatial clonal architecture, we performed multi-region whole-exome sequencing of radiology-guided fine-needle aspirates from 51 MM patients. We found spatial genomic heterogeneity in a substantial proportion of cases including bi-allelic inactivation of tumor suppressors and mutations affecting cancer genes. The amount of heterogeneous mutations associated with the size of focal tumor lesions in whole body imaging consistent with focal outgrowth of highly advanced clones. In conclusion, our results support the regional initiation of transformation processes leading to high-risk disease as well as the pre-existence of key driver events in restricted areas. As such, our study does not only provide new insights in the underlying biology of MM progression but also has considerable implications for standard diagnostic approaches in the clinic.

  Study EGAS00001002111

• Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

  Follicular lymphoma (FL) is an incurable B-cell malignancy characterized by the t(14;18) and mutations in one or more components of the epigenome. Whilst frequent gene mutations in signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlap with the closely-related diffuse large B cell lymphoma (DLBCL). A combination of discovery exome and extended targeted sequencing revealed recurrent somatic mutations in RRAGC uniquely enriched in FL patients (17%). More than half of the mutations preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar H+-adenosine triphosphate ATPase (v-ATPase) known to be necessary for amino acid-dependent mTORC1 activation. RagC mutants increased raptor binding whilst rendering mTORC1 signaling resistant to amino acid deprivation through nucleotide-independent mechanisms. Collectively, the activating nature of the RRAGC mutations, their existence within the dominant clone and stability during disease progression supports their potential as an excellent candidate to be therapeutically exploited.

  Study EGAS00001001190

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• Whole genome analysis of pediatric patients with medulloblastoma

  Cancer genomes often contain structural variations (SVs) in non-coding regions, while its impact on tumorigenesis is still unclear. Our goal is to discover genome folding changes resulted from SVs using InfoGenomeR and InfoHiC frameworks, which may reveal novel therapeutic targets. We applied our frameworks to five pediatric patients with medulloblastoma, revealing 3D genome changes of medulloblastoma driver genes.

  Study EGAS00001006653