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• Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing

  Background Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. Results We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant ‘normal’ cells or aberrant cells of unknown origin that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent, and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Conclusions Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

  Study EGAS00001002102

• Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

  This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000382

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance

  When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

  Study EGAS00001005876

• Genetic immune escape landscape in primary and metastatic cancer

  Immune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,457 uniformly processed Whole Genome Sequencing (WGS) tumor samples including 58 cancer types from 1,943 primary untreated patients and 4,514 metastatic patients. To effectively address the complexity of the Human Leukocyte Antigen (HLA-I) locus and to characterize its tumor status, we developed LILAC, an open-source integrative framework. We demonstrate that one in four tumors harbor GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is highly consistent between primary and metastatic tumors for most cancer types with few exceptions such as prostate and thyroid carcinomas that have increased immune evasion frequencies in metastatic tumors. Positive selection analysis revealed that GIE alterations are frequently selected for in tumor evolution and that focal LOH of HLA-I, unlike non-focal LOH of HLA-I, tends to lose the HLA allele that presents the largest neoepitope repertoire. We also unraveled tumor genomic features contributing to immune escape incidence, including DNA repair deficiency, APOBEC activity, tobacco associated mutation load and viral DNA integration. Finally, there is a strong tendency for mid and high tumor mutation burden (TMB) tumors to preferentially select LOH of HLA-I for GIE whereas hypermutated samples favor global immune evasion strategies. Our results indicate that genetic immune escape is generally a pre-metastatic event during tumor evolution and that tumors adapt different strategies depending on their neoepitope burden.

  Study EGAS00001006123

• Dynamics of circulating tumor DNA in acute myeloid leukemia (AML) patients who undergo allogeneic transplantation

  Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for many patients with acute myeloid leukemia (AML). With the increasing use of non-myeloablative conditioning regimens, it is widely assumed that the cytotoxic conditioning itself does not eradicate all leukemia cells. Instead, the donor-derived immune cells are believed to eliminate residual leukemia cells over time. This so-called graft-versus-leukemia (GvL) is postulated to be the primary mechanism by which allo-HCT achieves sustained remissions in patients with AML. However, the precise quantification of GvL effects and its contribution to leukemia eradication has not yet been demonstrated by sequential, highly sensitive measurements of residual disease at various time points following allo-HCT. In the current study, we employed a novel, highly sensitive and specific plasma-based assay to track mutations in the leukemia cells of 14 patients before and after allo-HCT. If the primary therapeutic benefit of allo-HCT is truly mediated through a GvL effect, we hypothesized that leukemia cells would persist following cytotoxic conditioning and would often be reduced after post-transplant immunosuppression was discontinued. In the majority of patients (11 of 14, 79%), the conditioning used for allo-HCT did not eradicate the leukemia cells. In seven of these 11 patients, the leukemia cells persisted until immunosuppression was discontinued, at which time the persistent leukemia cells were reduced or eradicated. These results demonstrate the feasibility of using circulating tumor DNA (ctDNA) as a dynamic marker of GvL as well as minimal residual disease for patients with AML undergoing alloHCT, and have substantial implications for their management.

  Study EGAS00001007969

• Multi-omic analysis of Down Syndrome in thyroid

  Background: Down syndrome (DS) is a chromosomal disorder characterized by trisomy of chromosome 21 and is associated with various health problems. Congenital thyroid dysfunction is a common endocrine abnormality in DS, but its exact cause remains unknown. This work aimed at studying the etiology of congenital thyroid dysfunction in DS. Methods: Thyroid tissue of fetuses with DS (n=4) and fetuses without a genetic/developmental abnormality (n=5) were analyzed using histopathological evaluation, RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling. Results: Histological examination showed abnormally developed DS thyroid tissue compared to non-DS/healthy tissue. RNA-seq analysis showed numerous differences in gene expression between DS and healthy thyroid tissue, including significant downregulation of thyroid genes FOXE1, IYD and DIO2. Gene set enrichment analysis showed disruption of vital cellular processes and functions in DS fetal thyroid tissue. Analysis of DNAm and expression quantitative trait methylation (eQTM) analysis identified functional and biologically relevant associations, that can be linked to plausible disrupted pathways in DS. Conclusions: Based on these observations, we conclude that congenital non-autoimmune thyroid dysfunction in DS is probably a DS-specific form of thyroid dysfunction, characterized by abnormal thyroid development, altered expression of genes that regulate thyroid development and hormone production, and altered expression and DNAm of genes pertaining to numerous vital pathways leading to significant metabolic disturbances. The disturbances as investigated by multi-omics analyses (RNA-seq, DNAm and eQTM analyses) are widely spread over the genome, and presumably caused by the direct and downstream effects of overexpressed chromosome 21 genes (dosage effect), and (epi)genomic disturbances.

  Study EGAS00001007677

• Peking University BIOPIC Data Access Committee (PUBDAC).The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any academic research institutions complying with the laws and bioethic regulation policies of China will be approved.

  Dac EGAC00001000551

• Whole genome sequencing of Sinonasal hemangiopericytoma and patient derived cell line model

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1 using whole genome sequencing.

  Study EGAS50000000025

• Gut 16S rRNA/FINRISK 2002

  The main goal of the project is the study the associations between the gut 16S rRNA and human health. The dataset contains data for FINRISK 2002 participants (a random sample of individuals living in six geographic areas in Finland) who underwent fecal sampling.

  Study EGAS50000000198

• Brigham and Women's Hospital Multiple Sclerosis Genetic Collection

  The main objective of this GWA study is to identify Multiple Sclerosis (MS) susceptibility loci. Whole-genome association analysis was performed on 924 individuals genotyped on the Affymetrix 6.0 Genechip. The cohort consisted of 860 clinically diagnosed MS patients and 64 control subjects.

  Study phs000275

• The Placenta Harbors a Unique Microbiome

  This study is to investigate placental microbiome through 16S rDNA-based and whole genome shotgun metagenomic sequencing. Identified taxa and their gene carriage patterns were compared to other human body sites niches. The placental microbiome profiles were most akin to the human oral microbiome.

  Study phs000735

• Genetic Basis of Isolated Arhinia and Bosma Arhinia Microphthalmia Syndrome

  The goal of this project is to determine the genetic etiology of congenital arhinia and Bosma arhinia microphthalmia syndrome through a combination of whole-exome, whole-genome, and targeted sequencing followed by in silico, in vitro, and in vivo functional modeling.

  Study phs001246

• NHLBI TOPMed: Pulmonary Fibrosis Whole Genome Sequencing

  This is a set of cases diagnosed with idiopathic pulmonary fibrosis, a fatal interstitial lung disease. These cases were included in the TOPMed phase three studies. The planned study will compare these cases to within-TOPMed controls for genome-wide association studies.

  Study phs001607

• The molecular basis of inherited reproductive disorders

  The purpose of this study is to discover genetic mutations in patients who have GnRH deficient states. This includes individuals with variant forms of hypogonadotropic hypogonadism, including individuals who have somatic anomalies involving mid-line facial defects, renal agenesis, synkinesia, and ataxia, amongst others.

  Study phs000475

• Whole-Genome and Exome Sequencing in clear-cell Renal Cell Carcinoma (ccRCC)

  Study to evaluate the molecular genetics of ccRCC through integrative analyses of tumors and tumorgrafts using multiple platforms in clinically annotated samples. Genome and exome data for patients giving consent to have the information available on a public, secure, database is being submitted.

  Study phs000491

• Etiologic Studies of Macular Degeneration

  This is a genotyping study of selected participants in an ongoing study of macular degeneration and related ocular disorders. DNA samples were obtained from 1985 (study initiation) to 2018. Phenotypes were determined using the validated Clinical Age-Related Maculopathy Grading System (Ophthalmol 2006, PMID 16458093).

  Study phs001896

• Phase 2 Study of Pembrolizumab in Combination with Gemcitabine and Cisplatin as Neoadjuvant Therapy

  The purpose of the clinical trial (NCT02690558) is to evaluate whether adding pembrolizumab (Keytruda) to the combination of gemcitabine and cisplatin will improve shrinkage of the tumor before having a cystectomy, for people with muscle-invasive bladder cancer (MIBC).

  Study phs003452

• E05-Bioenvironmental Psychiatry

  The Bio-Environmental Psychiatry Group is made up of a group of clinical (psychiatry, neuroradiology) and basic (biology) researchers. The objective of our activity is the identification of determinants of mental disorders with the aim of devising interventions that improve the quality of life of patients with mental disorders. Our fields are the prediction of mental disorder, the premorbid and precise diagnosis of mental disorder, the identification of bio-environmental markers and the personalization of treatments. We also work with specific disorders such as Delusional Disorder, OCD, depression and personality disorders.

  Dac EGAC50000000222

• Moroccan Genome Project: Sequencing Data from 109 Whole Genomes of Moroccan Individuals

  This study is the first phase of the Moroccan Genome Project, which included the complete sequencing of 109 genomes from the Kingdom of Morocco. The sequencing was performing using the Illumina NovaSeq6000 platform, with a mean coverage of 30X.

  Study EGAS50000000529

• Transplant Outcomes in Aplastic Anemia (TOAA): GWAS and Whole Exome Sequence Data

  The TOAA study is a research collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research. The study aims to identify molecular predictors of outcomes after hematopoietic cell transplant in patients with severe aplastic anemia.

  Study phs001710

• ICARUS-BREAST01 Dataset

  A phase II clinical trial (NCT04965766) of patritumab deruxtecan in 99 breast cancer patients. Whole-exome sequencing (WES) is available for 43 tumor samples and 43 blood samples collected at entry into the trial. RNA-squencing is available for 44 samples comprising 22 samples collected at entry into the trial and 22 samples collected during treatment (cycle 1 day 3, cycle 1 day 19, or cycle 2 day 3) from 22 patients.

  Dataset EGAD50000000773

• Transrenal DNA Analysis

  Urinary cell-free DNA (ucfDNA) is an emerging marker in liquid biopsy. However, the characteristics of transrenal DNA and urinary-tract DNA are not fully understood. Therefore, we investigated the fragmentomic features and demonstrated the potential clinical utilities of ucfDNA in the current study.

  Study EGAS50000000766

• Comprehensive genomic characterization of early stage bladder cancer - nanopore sequencing

  For this project about non-muscle invasive bladder cancer (NMIBC), we analysed long read sequencing data from 4 patients using the Nanopore platform. The dataset is composed of 8 BAM files: 4 tumor samples and 4 paired blood samples.

  Study EGAS50000000510

• Comprehensive genomic characterization of early stage bladder cancer - shallow whole genome sequencing data

  For this project about non-muscle invasive bladder cancer (NMIBC), we analysed shallow WGS data from 362 patients. The dataset is composed of 392 BAM files: 362 tumor samples, 15 female normal samples and 15 male normal samples.

  Study EGAS50000000513