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• Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes

  Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past few decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated. However, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present an orthotopic xenotransplantation model of human patient-derived PDAC organoids in which organoids are grafted via direct injection into the pancreatic duct of immunocompromised (NSG) mice. Tumors that arise from these intraductally grafted organoids (IGOs) enable the distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively, depending on which organoid they originate from. RNA-sequencing was used to characterize the tumors that resulted from IGO xenografts, and to compare the fast- and slow-progressing IGO tumors. Tumors generated using a traditional orthotopic xenograft model, in which organoids are injected into the parenchyma of the pancreas (i.e. orthotopically grafted organoids, or OGOs), were also sequenced for comparison with the IGO tumors. To further characterize the model, laser-capture microdissection followed by RNA-sequencing was used to compare intraductal to invasive lesions resulting from IGOs. To better understand the connection between KRAS signaling and the fast-progressing phenotype, RNA-sequencing was used to compare cultured organoids in which oncogenic KRAS (GeneID: 3845) was hyperactivated to control organoids, and to compare laser-capture microdissected lesions derived from IGOs of KRAS-hyperactivated organoids to lesions derived from control organoids. To ascertain copy number, low-coverage, whole genome DNA-sequencing was performed on organoids cultured in vitro, and on laser-capture microdissected lesions derived from IGO tumors.

  Study phs002045

• Genome_Diversity_in_Africa_Project___GemCode_libraries

  Globally, human populations show structured genetic diversity as a result of geographical dispersion, selection and drift. Understanding this genetic variation can provide insights into the evolutionary processes that shape both human adaptation and variation in disease. Populations from Africa have the highest levels of genetic diversity. This characteristic, in addition to historical genetic admixture, can lead to complexities in the design of studies assessing the genetic determinants of disease and human variation. However, such studies of African populations are also likely to provide new opportunities to discover novel disease susceptibility loci and variants and refine gene–disease association signals. A systematic assessment of genetic diversity within Africa would facilitate genomic epidemiological studies in the region.The Genome Diversity in Africa Project (GDAP) will extend and expand the African Genome Variation (AGV) project, an international collaboration aimed to produce a comprehensive catalogue of human genetic variation in Sub-Saharan Africa (SSA). Using a sequencing-based approach, GDA project aims to capture human genetic variation in Africa, including single nucleotide polymorphisms (SNPs), structural variants, and haplotypes. This resource will make a substantial contribution to understanding patterns of genetic diversity within and among populations in Africa, as well as providing a global resource to help design, implement and interpret genomic studies in African populations and studies comprising globally diverse populations, complementing existing genomic resources. Specifically, we plan to carry out whole genome sequencing at high depth (30x) of up to 1000 individuals across Africa (25 individuals from each ethnolinguistic group). We have already completed sequencing from 5 ethno-linguistic groups and we are now adding others.Our scientific objectives are to: 1) develop a resource that provides a comprehensive catalogue of genetic variation in populations from Africa accessible to the global scientific community; 2) characterise population genetic diversity, structure, gene flow and admixture across Africa; 3) develop a cost-efficient, next-generation genotype array for diverse populations across Africa; and 4) facilitate whole genome-sequencing association studies of complex traits and diseases by developing a reference panel for imputation and resource for enhancing fine-mapping disease susceptibility loci. These scientific objectives will be supported by cross-cutting operational activities, including network and management of the consortium, research ethics, and research capacity building in statistical genetics and bioinformatics.

  Study EGAS00001001589

• Dataset for WGS and RNA samples of acute myeloid leukemia with MNX1 expression (non-hipo)

  This dataset contains 115 samples of WGS, ATAC, 4C and RNAseq samples of patients with acute myeloid leukemia. The sequencing was performed on Illumina HiSeq 4000, 2000 and HiSeq X using Illumina TruSeq Nano DNA and Agilent Strand Specific RNA Kits. The sequencing was always paired.

  Dataset EGAD50000001097

• Fetal origins of malignant germ cell tumours

  Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells (PGCs). They are uniquely able to generate embryonic and extraembryonic tissues, which in malignant GCTs carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we studied the phylogenetic and transcriptional diversity of 15 malignant gonadal GCTs and four normal testis biopsies by sequencing 131 whole genomes and 416 transcriptomes from 14 gonadal histologies, excised by laser capture microdissection. Our findings demonstrate that tumours were initiated by whole genome duplication likely in embryogenesis, within ~5-8 cell divisions post-PGC specification, followed by chromosome 12p gains associated with invasive disease. Of note, 12p imbalances were not only generated through GCT-typical isochromosomes, but also through non-isochromosomic configurations. Whilst tumours developed along homogenous phylogenetic pathways, they spawned manifold tissues independent of genetic subclonal diversification. A key feature of GCT tissues was the expression of fetal-specific genes. The transcriptional diversity notwithstanding, we found universal transcriptional elements correlated with hallmark 12p gains. Overall, our study reveals stereotyped phylogenies and transcriptomes underpinning the development of GCT that originate in fetal life and may lend themselves to therapeutic manipulation.

  Dataset EGAD00001007038

• Novel driver variants in the histone 3.3 genes, H3F3A and H3F3B, define bone and cartilage cancer sub-types

  A selection of human cancers harbours somatic driver mutations in genes encoding histones, most notably childhood brain tumours with K27M substitutions of the histone 3.3 gene, H3F3A. We performed whole genome sequencing of the benign cartilage tumour, chondroblastoma, and targeted sequencing of histone 3.3 genes, H3F3A and H3F3B, in seven further skeletal tumour types. We identified an exceptionally high prevalence of novel histone 3.3 driver mutations at glycine 34 and at lysine 36. Histone 3.3 gene mutations were found in 91% in giant cell tumours of bone (48/53), mainly H3F3A G34W variants, and in 92% of chondroblastoma (73/79), predominantly K36M mutations in H3F3B. H3F3B is paralogous to the cancer gene H3F3A. However, H3F3B driver variants have not previously been reported in human cancer. Our observation demonstrate remarkable tumour-specificity of mutations, with respect to which histone 3.3 gene and residue is mutated, indicating that the advantage these mutations confer is tumour dependent. Moreover, tumour-specific mutation of H3F3A and H3F3B suggests, that although both genes encode identical proteins, they are likely non-redundant and employed differentially during skeletal development.

  Dataset EGAD00001000646

• Characterization of a human iPSC-derived islet differentiation model

  To explore the contribution of islet development to T2D pathogenesis, we characterised the transcriptomes of 3 human iPSC lines (from independent donors) differentiated along the islet development lineage. Whole transcriptome RNA-seq was performed at 7 developmental stages: definitive endoderm, primitive gut tube, posterior foregut (PF), pancreatic endoderm, endocrine progenitors, endocrine-like cells, and beta-like cells (BLC). Differentially-expressed (ΔExp) genes were assigned to the stage in which they were most upregulated (versus baseline iPSC profile), and used to assess the enrichment of T2D GWAS genes, as well as to predict the upstream transcription factors at each developmental stage.We found 9409 ΔExp genes across all stages, including known markers of islet development (NEUROG3, INS). Genes ΔExp in the most-differentiated (BLC) stage were significantly enriched for genes within the 99% credible sets of T2D GWAS loci. Despite this enrichment in BLC only, over 70% of genes mapping within the credible sets were ΔExp before this stage, highlighting the relevance of key T2D GWAS genes in islet development: e.g. expression of TCF7L2 peaked during the PF stage (log2FC=1.2; q=8.5×10-10). REST and LMNA are also highlighted by the analyses as having a potential function in islet development, considering their pattern of expression and those of the genes they regulate. Transcriptomic signatures derived from this iPSC differentiation model highlight T2D-associated GWAS loci, monogenic diabetes genes and potential master regulators of gene networks with plausible function in islet development. All these provide clues for developmental mechanisms contributing to T2D diabetes pathology.

  Study EGAS00001002721

• The Gene Partnership (TGP) - eMERGE Data

  The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants' preferences; results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP.

  Study phs000495

• Dataset for desmoplastic small round cell tumor - RNA

  This dataset contains 32 RNA sequencing samples of patients with desmoplastic small round cell tumor. Sequencing was performed on Illumina HiSeq 2500, Illumina HiSeq 4000, Illumina HiSeq X and NovaSeq 6000 using Illumina TruSeq RNA and TruSeq Stranded RNA Kit. The sequencing was always paired.

  Dataset EGAD50000000912

• Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined with Nivolumab and Ipilimumab for Patients with Resected MMR-p Colorectal and Pancreatic Cancer

  We developed INtraCEllular Reverse Transcription with Sorting and sequencing (INCERTS), an approach to combine molecular indexing of receptor repertoires within intact cells and fluorescence-activated cell sorting (FACS). We demonstrate that INCERTS enables efficient processing of millions of cells from pooled human peripheral blood mononuclear cell (PBMC) samples while retaining robust association between T cell receptor (TCR) sequences and cellular phenotypes. We used INCERTS to discover antigen-specific TCRs from patients with cancer immunized with a novel mutant KRAS peptide vaccine. After ex vivo stimulation, 28 uniquely barcoded samples were pooled prior to FACS into peptide-reactive and non-reactive CD4+ and CD8+ populations. Combining complementary patient-matched single-cell RNA sequencing (scRNA-seq) data enabled retrieval of full-length, paired TCR alpha and beta chain sequences for future validation of therapeutic utility. Data available through dbGaP include scRNA-seq with matched TCR-seq.

  Study phs003425

• Tumor-reactive heterotypic CD8 T cell clusters from clinical samples

  Emerging evidence suggests a correlation between CD8+ T cell-tumor cell proximity and anti-tumor immune response. However, it remains unknown whether these cells exist as functional clusters that can be isolated from clinical samples. By conventional and imaging flow cytometry, we show here that from 21/21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing revealed that T cells from clusters were enriched for gene signatures associated with tumor reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, while TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than to tumor cells. T cells that were expanded from clusters ex vivo exerted on average 9-fold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. Upon adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single cell gating in flow cytometry, these distinct heterotypic T cell clusters serve as a valuable source to decipher functional tumor-immune cell interactions, while they may also be therapeutically explored.

  Study EGAS50000000785