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• TRACERx Reduced-representation bisulfite sequencing (RRBS)

  RRBS data from TRACERx non-small cell lung cancer (NSCLC) tumours and matched normal adjacent tissue. TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC).

  Dataset EGAD00001009707

• Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

  Whole-genome sequence (WGS) analysis of tumors from 22 TP53 mutation carriers. We observed somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identified near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurred earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, revealed that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising very early in life or in utero.years prior to tumor diagnosis.

  Dataset EGAD00001009280

• A living biobank of breast cancer organoids captures disease heterogeneity

  Breast Cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Xeno-transplantation and direct culturing of tumor tissue are increasingly used in drug development and personalized medicine strategies. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, 101 BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor-, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene expression-based classification groups and allowed drug screens in vitro and upon xenotransplantation. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.

  Study EGAS00001002158

• Adult human kidney organoids originate from CD24+ cells and represent an advanced model for adult polycystic kidney disease

  Adult kidney organoids have been described as strictly tubular epithelial and termed tubuloids. While the cellular origin of tubuloids has remained elusive, here we report that they originate from a distinct CD24+ epithelial subpopulation. Long-term-cultured CD24+-derived tubuloids represent a functional human kidney tubule. We show that kidney tubuloids can be used to model the most common inherited kidney disease, namely autosomal dominant polycystic kidney disease (ADPKD), reconstituting the phenotypic hallmark of this disease with cyst formation. Single-cell RNA sequencing of CRISPR/Cas9 gene-edited PKD1 and PKD2 knockout tubuloids and human ADPKD and control tissue show similarities in upregulation of disease-driving genes. Furthermore, in a proof of concept, we demonstrate that tolvaptan, the only approved drug for ADPKD, shows a significant effect on cyst size in tubuloids but no effect in a pluripotent-stem-cell-derived model. Thus, tubuloids derive from a tubular epithelial subpopulation and represent an advanced model for ADPKD disease modeling.

  Study EGAS00001006551

• Preferential infiltration of unique Vγ9Jγ2‐Vδ2 T cells into glioblastoma multiforme

  Glioblastoma multiforme (GBM) is clinically highly aggressive as a result of evolutionary dynamics induced by cross-talk between cancer cells and a heterogeneous group of immune cells in tumor microenvironment. The brain harbors limited numbers of immune cells with few lymphocytes and macrophages; thus, innate‐like lymphocytes, such as γδ T cells, have important roles in antitumor immunity. Here, we characterized GBM‐infiltrating γδ T cells, which may have roles in regulating the GBM tumor microenvironment and cancer cell gene expression. V(D)J repertoires of tumor‐infiltrating and blood‐circulating γδ T cells from four patients were analyzed by next-generation sequencing-based T-cell receptor (TCR) sequencing in addition to mutation and immune profiles in four GBM cases. In all tumor tissues, abundant innate and effector/memory lymphocytes were detected, accompanied by large numbers of tumor‐associated macrophages and closely located tumor‐infiltrating γδ T cells, which appear to have anti-tumor activity. The immune-related gene expression analysis using the TCGA database showed that the signature gene expression extent of γδ T cells were more associated with those of cytotoxic T and Th1 cells and M1 macrophages than those of Th2 cells and M2 macrophages. Although the most abundant γδ T cells were Vγ9Vδ2 T cells in both tumor tissues and blood, the repertoire of intratumoral Vγ9Vδ2 T cells was distinct from that of peripheral blood Vγ9Vδ2 T cells and was dominated by Vγ9Jγ2 sequences, not by canonical Vγ9JγP sequences that are mostly commonly found in blood γδ T cells. Collectively, unique GBM‐specific TCR clonotypes were identified by comparing TCR repertoires of peripheral blood and intra‐tumoral γδ T cells. These findings will be helpful for the elucidation of tumor-specific antigens and development of anticancer immunotherapies using tumor-infiltrating γδ T cells.

  Dataset EGAD00001004862

• Motif-directed chromatin repression by BCL11B shapes ectopic targeting and lineage commitment

  BCL11B encodes a critical T-lineage transcription factor that is implicated as both an oncogene and a tumor suppressor in acute leukemia. Despite its central role in development and malignancy, a basic understanding of the sequence determinants of BCL11B activity remains obscure. Here, we define two functionally distinct modes of BCL11B engagement with chromatin: Most detectable BCL11B binding events are determined by pre-existing patterns of chromatin accessibility and RUNX1 occupancy. In contrast, BCL11B directs chromatin closing at genomic regions enriched for DNA motifs containing the core “TGACC” sequence, which are most prevalent in non-T lineages. These BCL11B-closed target sites cannot be identified from conventional BCL11B chromatin profiling approaches yet represent the primary mechanism by which BCL11B regulates gene expression. We provide evidence that cell of origin impacts the ability of BCL11B to repress lineage-inappropriate gene programs, thereby promoting lineage skewing. Together, these findings define a motif-centered determinant of BCL11B repression and explain how BCL11B controls lineage specification.

  Study EGAS50000001719

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• Systemic Inflammation and Lymphocyte Activation Precede Rheumatoid Arthritis

  The Allen Institute for Immunology-University of California, San Diego-University of Colorado Transition to Rheumatoid Arthritis (ALTRA) project is a prospective longitudinal cohort study to understand the pre-clinical development of rheumatoid arthritis (RA). We performed cross-sectional and longitudinal multi-omics analyses of peripheral immunity in the anti-citrullinated protein autoantibody-positive (ACPA+) at-risk for RA period. We provide FASTQ files from (1) single-cell RNA sequencing (scRNA-seq) of ACPA+ at-risk (n=45), ACPA+ early RA (n=11), and site-matched ACPA- controls (n=38); (2) scRNA-seq of longitudinal samples from ACPA+ at-risk who developed clinically active RA during our study (n=16 participants, n=75 samples) and ACPA- controls (n=29 subjects, n=89 samples); (3) trimodal TEA-seq of a subset of ACPA+ at-risk (n=7) and ACPA- controls (n=5). Using these data, we characterize pathogenesis prior to clinical RA diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity.

  Study phs003944

• Deciphering Developmental Disorders (DDD)

  The Deciphering Developmental Disorders (DDD) study is a research collaboration between the Wellcome Trust Sanger Institute, the NHS clinical genetics services and families across the UK and Ireland. The project aims to improve the diagnosis of children with developmental disorders by using high-resolution microarray and massively parallel sequencing technologies on 12,000 children and their parents. Genetic changes that explain the child's symptoms will be displayed in the DECIPHER database (https://decipher.sanger.ac.uk). Extended datasets generated by the DDD project will be available in the European Genome-Phenome Archive with access carefully managed by a Data Access Committee.

  Study EGAS00001000775

• CTCF/cohesin-binding sites are frequently mutated in cancer

  Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

  Study EGAS00001003010