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• Integrated Genomic, Epigenetic, and Expression Analyses of Ovarian Cancer Cell Lines

  Epithelial ovarian carcinoma of all subtypes has one of the worst outcomes of any human cancer. To improve our understanding of underlying biology and therapeutic possibilities in this disease, we performed whole genome sequencing, methylation, and expression analyses of a comprehensive set of 47 ovarian cancer cell lines representing different histologic tumor subtypes. Given the challenges of genomic analyses in tumors without matched normal samples, we developed novel approaches for detection of somatic alterations and used these to identify sequence, copy number, and rearrangement changes and integrated these with genome-wide epigenetic and expression alterations. Ovarian cancer cell lines had molecular changes in genes involved in cell cycle, PI3K, RAS, BRCA, chromatin regulating, and p53 pathways, and displayed global mutation and methylation changes similar to primary ovarian carcinoma. We identified alterations not previously implicated in ovarian cancer including amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and members of the TGF beta receptor pathway, including TGFBR2, SMAD3 and SMAD4, in-frame rearrangements of YAP1-MAML2 and IKZF2-ERBB4, and fusions involving MET, NF1, FBXW7 and CCND1. Integrating cell line alterations with dose-response data using three targeted therapies revealed novel molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, those with MYC amplifications to PARP inhibitor BMN673, and SMAD4 alterations to MEK inhibitor MEK162. Genome-wide analyses revealed intrachromosomal rearrangements as an improved measure of sensitivity to PARP inhibition compared to the homologous recombination defect (HRD) score. This study provides a comprehensive resource of molecular information for ovarian cancer cell line models and a pharmacogenomic platform for developing rational cancer therapeutic strategies.

  Study EGAS00001002998

• An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia (CML)

  Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

  Study EGAS00001001751

• Sequencing of paediatric High Grade Gliomas and DIPG

  Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are a phenotypically diverse collection of tumours which molecular profiling studies have refined into age- and location-based subgroups driven by unique genetic and epigenetic alterations. Despite this, the rarity of these tumours means individual studies are underpowered to investigate subgroup-specific changes and to identify low frequency events recurrently targeting specific pathways. We have collated genomic data from 143 unpublished cases up to 30 years of age along with those from 18 previously published datasets in an integrated analysis comprising 1067 unique patients across all anatomical compartments of the CNS, with histone mutation status available for 893 cases (n=67 H3.3G34R/V, n=316 H3.3K27M, n=68 H3.1/H3.2K27M). Distinct clinicopathological and molecular subgroups are defined by these histone mutations, with several novel co-segregating mutations identified through these aggregated analyses, including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups can be further refined by the presence of key oncogenic events (PDGFRA or EGFR amplification/mutations) or methylation profiles which molecularly more closely resemble pleomorphic xanthoastrocytoma or other low grade gliomas. The burden of genomic aberrations decreases with age, highlighting the infant population as biologically and clinically distinct. Across the whole cohort, we identify novel previously unrecognised pathway dysregulation in small subsets of tumours (e.g. splicing, WNT, immune response) which make up the umbrella classification of paediatric diffusely infiltrating gliomas. The integrated dataset helps to further define the molecular diversity of the disease, opening up novel avenues for biological study and providing a basis for functionally defined future treatment stratification.

  Study EGAS00001002314

• Whole exome sequencing (WES) of EBV- primary central nervous system lymphoma (PCNSL)

  This dataset contains whole exome sequencing (WES) of 29 HIV- EBV- primary central nervous system lymphoma (PCNSL) tumors and 5 activated B-cell-like PCNSL (ABC-PCNSL) and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cell lines (TK, HKBML, OCI-Ly3, HBL-1, TMD-8). Cases with secondary involvement of the CNS were excluded. DNA was extracted with AllPrep DNA/RNA FFPE kit and libraries were prepared using the Agilent SureSelect Human All Exon v6 + UTR kit. Paired end reads were aligned to GRCh37 using bwa mem v.0.7.17, and reads were sorted and duplicated were marked in the final BAM files. Access to this data is controlled. There are a number of steps that a researcher must take to obtain access to this data, including execution of a Data Access Agreement between the institutions. The process is overseen by the Technology Development Office; please contact our general email address TDOadmin@phsa.ca. Please only click the "request data" button on the EGA website after a Data Access Agreement is fully executed.

  Dataset EGAD50000000451

• WGS dataset of Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

  Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. The elevated mutational load at relapse can partly be explained by at least two therapy-related effects and a combination of therapy and underlying mismatch repair deficiency. However, our understanding of the type and timing of mutational mechanisms in relapsed ALL is limited, and it is unclear to what extent mutational processes contribute to disease progression. We collected a cohort of 29 Dutch ALL patients across multiple treatment protocols who had multiple relapses. Using whole genome sequencing of the sequential tumor samples of each patient we were able to distinguish the mutational processes active in relapsed ALL and could track the activity of mutational processes over time. This allowed us to investigate whether subtype-specific mutational processes at diagnosis can continue in relapse or emerge at relapse if absent in initial diagnosis. Furthermore, we assessed whether the activity of mutational processes contributed to disease development and relapse.

  Dataset EGAD00001015401

• Human Lung Tissue eQTL Study

  Genetic risks underlying respiratory diseases (e.g. COPD and asthma) are carefully studied by large genome-wide association studies (GWAS), where many loci were identified. In the post-GWAS era, the main challenge is to find the causal genes and pathways in GWAS-nominated chromosomal regions and to characterize etiology mechanism. The Lung eQTL Consortium is an international effort to systematically capture the genetic architecture of gene expression regulation in human lung. By studying lung specimens from 1,103 individuals of mostly European ancestry, we report a large number of genetic variants affecting gene expression in the lung, or lung expression quantitative trait loci (eQTL). These lung eQTLs will serve as an important resource to aid in the understanding of the molecular underpinnings of lung biology and its disruption in disease.

  Study phs001745

• Multimodal Mapping of the Immune Landscape in Human Pancreatic Cancer

  Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that has rendered it largely refractory to immunotherapy. We used single-cell RNA sequencing on patient tumors and matched blood, and we uncovered a previously unappreciated, complex environment of immune-suppressive cellular interactions. These experiments reveal immune checkpoint expression heterogeneity on individual patient T cells, with corresponding ligands on neoplastic and myeloid cells. TIGIT was upregulated on tumor infiltrating CD8+ T cells and was the only checkpoint receptor consistently expressed by exhausted CD8+ T cells. Clinical annotation of the samples revealed that the exhausted signature is most prominent in patients with advanced stages of disease. Our findings suggest individualized combination therapy, involving anti-TIGIT therapies, may be necessary to extend the benefits of immunotherapy to pancreatic cancer patients.

  Study phs002071

• International Genetics of Parkinson Disease Progression (IGPP) Consortium: EPIPARK and HBS2 Cohorts

  EPIPARK and HBS2 cohorts were analyzed as part of the International Genetics of Parkinson Disease Progression (IGPP) Consortium. EPIPARK is a population-based cohort to study non-motor symptoms in parkinsonism in the city of Lübeck, Germany led by Drs. Meike Kasten and Christine Klein. HBS2 is a recently enrolled subset of participants in the Harvard Biomarkers Study led by Dr. Clemens Scherzer (www.bwhparkinsoncenter.org/biobank) of 89 participants with a diagnosis of Parkinson Disease (PD). Genotyping with Illumina Infinium Multi-Ethnic Genotyping Arrays (MEGA chip) was performed by Dr. Scherzer, Harvard Medical School and Brigham and Women’s Hospital. 179 participants with a diagnosis of PD from EPIPARK and 89 participants with a diagnosis of PD from HBS2 met Q/C criteria were analyzed.

  Study phs002328

• National Sleep Research Resource (NSRR): Hispanic Community Health Study/Study of Latinos

  The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH) contributed to the first phase of the project. Raw polysomnography data are available from the HCHS/SOL Baseline visit and raw actigraphy data are available from the Sueño Ancillary visit. Primary HCHS/SOL data can be requested through dbGaP phs000810 Hispanic Community Health Study /Study of Latinos (HCHS/SOL).

  Study phs003543

• Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

  Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.

  Study EGAS00001005410