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• Bladder cancer sequencing data

  Dataset EGAD00001001036

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation patterns and terminal sequences of cell-free DNA (cfDNA) are altered by nucleases and biological mechanisms in the blood of cancer patients. The cfDNA fragment-end composition recovered from low coverage WGS (<1 fold coverage) using a bespoke software (FrEIA) is aberrant in the plasma from cancer patient (n = 418, 655 samples) compared to controls (n = 117). As a standalone test FrEIA allows detection down to ~0.2% tumor fraction in vitro and in silico at 95% specificity, leading to a sensitivity of ~71% for detecting lung cancer (14/22 stage I-II, 27/38 stage III, 92/127 stage IV) and ~68% for detecting esophageal adenocarcinoma (26/44 stage II, 46/62 stage III). Additional cfDNA biological patterns can be combined with FrEIA increasing the diagnostic potential of low coverage WGS at minimal cost (mean AUROC = 0.96). Integrating multiple cfDNA biological signal augments the diagnostic performance of liquid biopsy.

  Study EGAS00001006142

• Low-pass nanopore whole genome sequencing of brain tumors

  Dataset EGAD00001003382

• EuCANCan: EUropean-CANadian Cancer network

  The EUropean-CANadian Cancer network (EuCANCan) is a project aiming to develop a federated network of aligned and interoperable infrastructures for the homogeneous analysis, management and sharing of genomic oncology data for Personalized Medicine. This initiative, funded by the European Commission and the Canadian Institutes of Health and coordinated by the Barcelona Supercomputing Center (BSC), is expected to process and provide the scientific community with around 30-35 thousand patient samples from different types of cancer, coming from different nodes involved in this project, during the four years of the project. Data generated as part of primary studies, often in small hospitals or research centers, is hardly reused by other projects or groups. EuCANCan is proposed to foster the homogenisation and discoverability of cancer samples from very different sources for the whole community. These efforts will help paving the way to future standardised and global genomics projects, specially for those participant countries that eventually integrate the methodology and infrastructure generated during the project. “The more data we have access to the more and better discoveries. We attempt to overcome the legal and technical limitations in order to generate, gather and exploit bigger datasets as well as answer more ambitious questions”. These were some of the words Dr. David Torrents, main coordinator of the project, shared with a regional radio during the kick-off meeting of the project, on February 11th, 2019. The EUCANCan network will be composed of reference nodes in Amsterdam, Barcelona, Berlin, Heidelberg, Paris and Toronto which have established strong research and clinical programs in the field of genomic oncology. The Centre for Genomic Regulation (CRG), specifically the European Genome-phenome Archive (EGA), is among the leading institutions. Its exhaustive experience in biomedical data archival and secure distribution is considered key for crucial developments within the project. It is also notable the recent inclusion of EUCANCan in the list of GA4GH driver projects. Further information and details can be found in the following links: InsideHPC BSC official description Techweek (Spanish)

  Blog eucancan

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054

• Alcohol Dependence GWAS in European- and African Americans

  This study includes SSADDA (Semi Structured Assessment for Drug Dependence and Alcoholism) assessed subjects (mostly unrelated, but including some affected sibling pairs) recruited in the course of several substance dependence genetics projects. The sample includes 1889 African-American (AA) subjects and 1020 European-American (EA) subjects. Among the AAs, 1397 meet DSM-IV criteria for alcohol dependence and 491 are controls. Among the EAs, 1010 meet the criteria for alcohol dependence and 9 are controls. (One in each population meets criteria for alcohol abuse and not dependence, and is therefore counted in neither category.) Although alcohol dependence is the major focus, the sample is informative also for cocaine, nicotine, and opioid dependence.

  Study phs000425

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 40 samples matched to the WGS was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001009048

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 37 samples was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001010139

• Establishment of Human Trophoblast Stem Cells from Term Smooth Chorion

  Human trophoblast stem (TS) cells, which were established from blastocysts and first-trimester placental villi, can differentiate into the all trophoblastic subtypes, extravillous trophoblast (EVT) cells and syncytiotrophoblast (ST) cells. We newly generated human TS cells from the term smooth chorion (Ch-TS cells). They has the potential to differentiate into both ST and EVT cells as same as human TS cells derived from early placental villi. The transcriptomic profile of Ch-TS cells is also similar to conventional human TS cells.

  Study JGAS000777

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of patients with advanced metastatic melanoma, stage III(B-D)-IV, who were receiving treatment with anti-PD1 (n =26); and patients with kidney, non-small cell lung, liver and bladder cancer who were receiving treatment with anti-PD1. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.

  Dataset EGAD00001006415

• RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights

  To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and to identify new potential pathogenetic mechanisms, we performed transcriptome profiling by high-throughput sequencing. We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome, 17 adenomas with mild autonomous cortisol secretion, 9 endocrine-inactive adenomas, 7 adrenocortical carcinomas. Additionally, we sequenced 4 control samples.

  Study EGAS00001004533

• WES of der(1;7)(q10;p10)

  This dataset contains the BAM files of WES of 26 myeloid neoplasm patients with der(1;7)(q10;p10)(+) cases. The dataset was used to identify key driver genes in patients with der(1;7)(q10;p10). Already known drivers along with novel driver genes were identified through the use of this WES.

  Dataset EGAD50000000986

• Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

  We evaluated the utility of circulating tumor DNA (ctDNA) as a biomarker in the serum and urine of 50 patients with Stage III or Stage IV Wilms tumor (WT) that were enrolled on Children's Oncology Group (COG) trial AREN0533. 49 out of 50 patients had matched tumor samples available for comparison. We profiled samples with ultra-low pass whole genome sequencing (ULP-WGS) and detected ctDNA in 82% of serum samples and 26% of urine samples. We also identified copy-number changes and single-nucleotide variants in the serum and urine samples, and compared them to the tumor data. Our study highlights the advantages of using ctDNA as non-invasive prognostic biomarker with the potential to detect tumor heterogeneity in patients with WT. We believe that prospective validation of ctDNA as a prognostic biomarker in patients with WT is warranted. The ULP-WGS and targeted next-generation sequencing (OncoPanel) data are available in this study.

  Study phs002847

• Prostate cancer datasets WES

  WES: 48 samples (5 blood samples from 6 patient data): 22 Tumour cores and 26 normal/benign cores (HiSeq)

  Dataset EGAD00001004467

• Whole exome and Transcriptome sequencing of treatment-naïve esophageal adenocarcinoma biopsies and matched peripheral blood mononuclear cells

  Exome sequencing was performed on n=28 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. WES was performed on EAC biopsies at 120X average coverage, with autologous PBMCs used as germline controls at 80X average coverage. Libraries were prepared from 30 ng of input DNA using the SureSelect QXT Human All Exon V7 kit (Agilent Technologies) and sequenced on the NextSeq 550 (Illumina), 2x150 bp. BCL files were demultiplexed to FastQ files using bcl2fastq2 software (Illumina). Three paired end sequencing batches were analyzed independently (Batch1: samples 8, 10, 11, 12, 15, 17, 18; Batch2: samples 20, 24, 25, 26, 27, 29, 30, 31, 33, 34 ; Batch3: samples 35, 37, 39, 40, 41, 43, 45, 48, 54, 55, 57). RNA sequencing was performed on n=26 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. RNAseq libraries were prepared on 50 ng of total RNA (with RNA integrity index RIN >=7) with the TruSeq Stranded mRNA library preparation kit (Illumina) in accordance with low-throughput protocol. After PCR enrichment (15 cycles) and purification of adapter-ligated fragments, the concentration and length of DNA fragments were measured using D1000 Screen Tape System (Agilent), obtaining a median insert size of 311 nucleotides. Then, RNAseq libraries were sequenced using the Illumina NovaSeq platform, 1x100 bp, obtaining on average 100 million single reads per sample.

  Dataset EGAD00001010876

• Target sequencing of 27 cancer-predisposing genes and 13 renal cell carcinoma-related genes in Japanese renal cell carcinoma patients

  Identifying causative genes via genetic testing is useful for the screening, prevention, and treatment of cancer. Several hereditary syndromes are known to occur in renal cell carcinoma (RCC). However, these evidences came from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to the development RCC in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed using 1,563 Japanese patients with RCC and 6,016 controls. Patients were divided into two major histological subtypes of clear cell RCC (ccRCC) or non-clear cell RCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1,532 patients with RCC and 5,996 controls were further analyzed. For ccRCC, 52 of 1,283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 �� 10-4; OR, 5.8; 95% CI, 2.2���15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf), and FH (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf). Our study showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for better-personalized medicine.

  Study JGAS000414

• International Age-Related Macular Degeneration Genomics Consortium - Exome Chip Experiment

  Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. To further our understanding of AMD genetics, we examined the contribution of common and rare genetic variation in the International AMD Genomics Consortium that included ~50,000 samples of 26 AMD case - control cohorts that were jointly genotyped. Analyzing 16,144 patients with late stage AMD and 17,832 controls, we identified 52 independently associated common and rare variants distributed across 34 loci. Besides these single variant signals, we also observed gene-based enrichment of very rare coding variants (frequency < 0.1%) in cases that implicated causal roles for CFH, CFI and TIMP3 in three of the known AMD risk loci. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

  Study phs001039

• Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

  Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. Experimental design: RNA was extracted from metastasis biopsies obtained at study inclusion in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with RNA sequencing data. Lesions were compared based on the level of [89Zr]trastuzumab uptake (dichotomized into high/low classes) as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. Results: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases (one lesion/patient). Pathways involved in extracellular matrix (ECM) organization, glycosylphosphatidylinositol synthesis, and collagen formation were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions that showed no metabolic response to T-DM1. Interestingly, immune-related processes (e.g., Fc gamma receptor activation, complement cascade) were associated with high [89Zr]trastuzumab uptake and metabolic response. Conclusions: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings point toward a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, and highlight the potential of molecular imaging to depict tumor microenvironment features.

  Study EGAS50000000470

• Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objectives To test whether pulmonary artery catheter use was safe and could improve clinical outcomes in participants hospitalized with recurrent heart failure. Background Pulmonary artery catheters have been used to guide adjustment of therapy in multiple settings, but recent studies have raised concern that pulmonary artery catheters may lead to increased mortality in hospitalized participants. Participants A total of 433 participants at 26 sites were enrolled, and randomly assigned to receive therapy guided by clinical assessment and the pulmonary artery catheter or clinical assessment alone. Patients with acute decompensation in which the attending heart failure physician considered pulmonary artery catheterization (PAC) was required or likely to be required within the next 24 hours were entered into a PAC registry. A total of 439 patients were added to the registry. Conclusions Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures, with or without the pulmonary artery catheter. Addition of the pulmonary artery catheter to careful clinical assessment did not impact overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by participants. (Binanay, C. et al., JAMA, 2005)

  Study phs003782

• Duplex sequencing of 26 genes

  Buccal samples and paired esophageal epithelium were obtained using the three sizes of swabs and endoscopic biopsy, respectively. Forty samples from 10 subjects were analyzed via duplex sequencing. This dataset contains bam files that were mapped to the GRCh37 reference genome.

  Dataset EGAD50000000998

• Evolution of Structural Rearrangements in Prostate Cancer Intracranial Metastases

  Intracranial metastases in prostate cancer are uncommon but clinically aggressive. We sought to characterize prostate cancer intracranial metastases in order to improve our understanding of their pathogenesis and to promote the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) on samples from 21 patients. The WGS samples include 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n=6) and non-brain prostate cancer metastases (n=26).

  Study phs003357

• CPC-GENE Prostate Cancer Heterogeneity Study

  Raw sequence data, fastq format

  Dataset EGAD00001002885

• Small‑scale mutations are infrequent as mechanisms of resistance in post‑PARP inhibitor tumour samples in high grade serous ovarian cancer

  Targeted DNA sequencing of high-grade serous ovarian cancer (HGSC) tumour and normal samples from 26 patients. Following target hybrid capture of 63 genes involved in DNA repair and response to treatment with an Agilent SureSelect XT panel, sequencing libraries were generated using the SureSelect XT Low Input Target Enrichment System (Agilent) as per the manufacturer's protocol. Libraries were sequenced on an Illumina NextSeq 500 at the Peter MacCallum Cancer Centre (Melbourne, Australia).

  Study EGAS50000000146

• Transcriptomic profiling of patient-derived xenografts and organoids in prostate cancer

  Dataset contains RNA-seq of 30 samples (normal prostate tissue, human prostate cancer, PDX and organoids).

  Dataset EGAD00001006404

• Transcriptomic Analysis of Human Hematopoietic Progenitors from Healthy Donors and Bone Marrow Failure Patients

  The purpose of this study was to define transcriptional changes that occur in the rare and heterogeneous bone marrow progenitors that are affected in Shwachman-Diamond Syndrome. Data are reported for four genetically confirmed SDS patients ranging from 11-26 years old, 3 male and 1 female, and four healthy donors ranging from 25-29 years old, 2 male and 2 female. Subjects provided written, informed consent in accordance with the Declaration of Helsinki's Ethical Principles of Medical Research Involving Human Subjects. Single CD34+ cells were purified from fresh bone marrow and cDNA libraries were prepared using the SMARTer Ultra Low RNA Kit (Clontech; pre-2015) or SMART-Seq v4 Ultra Low RNA Kit (Clontech; post-2015). Libraries were sequenced on a HiSeq 2500 Instrument (Illumina, San Diego, CA) to a read depth of ~3 M paired-end, 25 bp reads per single cell. Paired-end reads were mapped to the hg38 human transcriptome (Gencode v24) using STAR v2.4.2a.

  Study phs001845