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• LBC1936 VCF

  LBC1921 and LBC1936 GVCFs called with GATK's HaplotypeCaller were combined and subject to variant quality score recalibration. This VCF contains the subset of samples (n = 1068) from the LBC1936 cohort.

  Dataset EGAD00001005478

• Gene expression in human monocyte differentiation

  This dataset consists of RNA-seq data data from human monocytes, monocyte-derived dendritic cells or monocyte-derived macrophages as well as monocyte-derived cells that were subjected to siRNA treatment targeting TET2, IRF4 and EGR2. In total, it includes 43 samples.

  Dataset EGAD00001006604

• Non-small cell lung cancer targeted sequencing

  Targeted sequencing of non-small cell lung cancer samples. BAM files of paired end reads aligned to hg19 using BWA MEM v0.7.1573. This targeted panel covers 370 genes of clinical relevance in non-small cell lung cancer.

  Dataset EGAD00001007918

• SMRT-seq

  In this study, we enhanced 5mC detection using SMRT sequencing by holistically analyzing kinetic signals of a DNA polymerase and sequence context for every base within a measurement window. We employed a convolutional neural network to train a methylation classification model.

  Dataset EGAD00001006875

• Exome Sequencing of 44 subjects with very severe or fatal COVID-19

  In this study, the DNA of 44 subjects with severe COVID-19 have been sequenced in order to explore rare genetic variants.

  Dataset EGAD00001008993

• Whole exome sequencing of 3 primary Plasma Cell Leukemia samples

  Primary plasma cell leukemia (pPCL) samples were sequenced using the Nimblegen MedExome Plus hybridization capture to detect translocations, copy number changes, and mutations in 3 pPCL samples and patient matched controls. Sequencing was performed on a NextSeq500 using 75 bp paired end reads.

  Dataset EGAD00001005306

• HV31 - Bionano DLS optical mapping

  Bionano DLS optical mapping data for individual HV31 generated using DNA from peripheral blood mononuclear cells, to a molecule depth of ~153×. Optical mapping was performed at the Weatherall Institute of Molecular Medicine using the Bionano Saphyr platform.

  Dataset EGAD00001007049

• Transcription factor binding in human monocyte differentiation

  This dataset consists of ChIP-seq data data from human monocytes, monocyte-derived dendritic cells as well as monocyte-derived cells that were subjected to mRNA transfection for PU.1, IRF4, and EGR2. In total, it the data set includes 18 samples.

  Dataset EGAD00001006602

• PacBio HiFi sequencing of telobait-captured DNA from 48 patients

  PacBio HiFi sequencing was performed on 48 barcoded patients' genomic DNA after a telobait-capture protocol to enrich for telomeric regions. The sequencing reads of each patient were de-multiplexed and presented as patient-specific PacBio CCS BAM files.

  Dataset EGAD00001008626

• Dataset for Ewing_sarcoma_PNET-WHOLE_GENOME

  Rare cancer sequencing data of 18 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008874

• Dataset for colorectal_cancer-WHOLE_GENOME

  Rare cancer sequencing data of 54 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008872

• Chromatin accessibility in human monocyte differentiation

  This dataset consists of ATAC-seq data from human monocytes, monocyte-derived dendritic cells or monocyte-derived macrophages as well as monocyte-derived cells that were subjected to siRNA treatment targeting TET2, IRF4 and EGR2. In total, it includes 26 samples.

  Dataset EGAD00001006601

• Gene expression in LPS-stimulated human monocyte-derived macrophages

  This dataset consists of RNA-seq data from human monocyte-derived macrophages that were subjected to siRNA treatment targeting RAD21 and either left untreated, or stimulated with LPS. In total, it includes 24 samples.

  Dataset EGAD00001007952

• Dataset for LCPlus_WES

  WES/WGS sequencing data of 86 chromothriptic tumor and control runs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001009273

• Epigentic sequence data of monocytes and macrophages

  Data for paper: Epigenetic dynamics of monocyte to macrophage differentiation with Chip Seq, NOMe, mRNA, total RNA, noncoding RNA, whole genome bisulfite seq,

  Dataset EGAD00001002201

• MDS primary and xenografted samples

  This dataset contains bam files mapped to hg19 that either were primary bone marrow cells or sorted human cells after long term engraftment in NSG mice.

  Dataset EGAD00001007760

• Dataset for NSCLC-EXON

  Rare cancer sequencing data of 42 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008892

• CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) of CLL_24

  To explore intratumor-heterogeneity of CLL_24 using single-cell multi-omics approach, we generated single-cell CITE-seq data for CLL_24, coupling scRNA-seq and protein surface marker measurements with oligo-tagged antibodies.

  Dataset EGAD00001009174

• Benchmarking CRISPR Whole-genome Drop-out Screen - B&S (2019-08-07)

  This study is a benchmarking exercise to explore potential source of variation between different CRISPR drop out libraries. . This dataset contains all the data available for this study on 2019-08-07.

  Dataset EGAD00001005233

• Familial adult myoclonic epilepsy type 1 in Sri Lankan and Indian families

  Whole genome sequencing data from four affected and one unaffected individuals from two families with familial adult myoclonic epilepsy, one of Sri Lankan origin and one of Indian origin. BAM files aligned to hg19 reference genome.

  Dataset EGAD00001005777

• COVID-19 Postmortem Lung snRNA-seq

  A deeper understanding of the pathological mechanisms of SARS-CoV-2 infection is required to combat COVID-19. Through this dataset, we analyze postmortem lung cells from patients that are infected/uninfected with SARS-CoV-2 with snRNA-seq.

  Dataset EGAD00001006584

• HV31 - PacBio long-read circular consensus (CCS) senquencing

  PacBio long-read circular consensus (CCS) sequencing data for individual HV31 generated on PacBio Sequel II instrument, using size-selected (10-15 kb) DNA from CD14+ monocytes, to a sequencing depth of ~12×. Sequencing was performed at the Wellcome Sanger Institute.

  Dataset EGAD00001006979

• CLL targeted exome sequencing (2018-03-14)

  Aim to characterise cancer gene landscape in CLL, particularly in cases with mutated POT1 gene. Treatment-naive CLL cases will be interrogated by targeted exome sequencing using a cancer gene panel. . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004037

• WXS from GBM-719 xenografts

  WXS from barcoded cells that are FACS sorted from GBM-719 xenografts, and the germline reference from patient GBM-719. The 4 xenografts are named according to passage (secondary or tertiary) and treatment (vehicle control or temozolomide).

  Dataset EGAD00001003422

• HERBY trial RNASeq

  RNA sequencing of non-brainstem paediatric high grade glioma from the HERBY phase II randomised trial. RNA from fresh frozen surgical tissue in 20 cases was subjected to Illumina whole transcriptome paired end sequencing. Data is provided as paired-end FASTQ files

  Dataset EGAD00001004070

• Shwachman-Diamond syndrome (SDS) Exome sequencing

  Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, leukemia predisposition, and skeletal abnormalities. We aim to characterise the structural effects of SDS in patients with this disorder by exome sequencing.

  Dataset EGAD00001000847

• BLUEPRINT Epigenetic characterization of megakaryocytes and erythroblasts

  Megakaryocytes and erythroblasts derive from the same progenitor cell type but carry out very different functions. In order to understand how the different functional phenotypes arise we have characterised the epigenetic landscape of these cells.

  Dataset EGAD00001001871

• CancerSEEK ctDNA FASTQ files

  Sequencing data from 1,005 cancer patients and 812 healthy controls. All samples prepared using Safe-SeqS technology and sequenced on an Illumina MiSeq and/or HiSeq instrument. Paired FASTQ files for correspond to read 1 and the index read present (R and I respectively).

  Dataset EGAD00001003931

• TRACERx pilot study, phase 2

  Multi-region Illumina whole-exome and/or whole-genome sequencing on tumor regions collected from early-stage NSCLC patients who underwent definitive surgical resection prior to receiving adjuvant therapy.Patients covered by this dataset: L012, L013, L015, L017

  Dataset EGAD00001001918

• Deep-Seq: Resistance to anti-EGFR therapy in colorectal cancer

  In this study we performed ultra deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR in 17 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy.

  Dataset EGAD00001000688

• Primary plasma cell leukemia genomic abnormalities

  Primary plasma cell leukemia (pPCL) samples were sequenced using the Nimblegen MedExome Plus hybridization capture to detect translocations, copy number changes, and mutations in 20 pPCL samples and patient matched controls. Sequencing was performed on a NextSeq500 using 75 bp paired end reads.

  Dataset EGAD00001004323

• ICGC-LIRI-JP Release 15

  RIKEN collection WGS reads for 321 HCC and blood matched samples from 158 donors submitted to ICGC for release 15

  Dataset EGAD00001000808

• IBDCA_Edinburgh

  In this experiment we have sequenced tumour normal pairs from patients presenting with CRC who have a prior history of inflammatory bowel disease. The idea is to identify driver mutations, new genes and novel pathways associated with the development of these malignancies.

  Dataset EGAD00001001330

• Human Evolution 3

  The mtDNA and Y chromosome of up to 15 Australian Aborigines, concentrating on individuals with indigenous lineages, will be sequenced using the standard whole-genome sequencing followed by filtering out of autosomal and X sequences, so that only mtDNA and the Y chromosome will be analysed and released.

  Dataset EGAD00001001373

• Metastatic Breast Cancer Whole Genome

  We propose to definitively characterise the somatic genetics of Metastatic breast cancer through generation of comprehensive catalogues of somatic mutations in Metastatic breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Dataset EGAD00001000899

• Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

  We used targeted sequencing to capture and measure the abundance as well as the size profiles of EBV DNA in plasma of subjects with and without NPC

  Dataset EGAD00001004204

• Genomic alteration in Korean Young Age Diffuse Gastric Cancers

  To identify recurrent somatic alterations in this unique subset of gastric cancers, whole exome and SNP6 analyses were performed using frozen cancer tissue. The somatic mutation analyses were also performed using blood of the same patients.

  Dataset EGAD00001001984

• Butyrate producers as potential next-generation probiotics: safety assessment of the administration of Butyricicoccus pullicaecorum to healthy volunteers

  Advances in gut microbiota research have triggered interest in developing colon butyrate producers as niche-specific next-generation probiotics, targeted at increasing colon butyrate production and countering disease-associated microbiota alterations. Crucial steps in the development of next-generation probiotics are the design of formulations with a reasonable shelf life as well as the safety demonstration of an intervention in healthy volunteers. One such potential next-generation butyrate-producing probiotic is Butyricicoccus pullicaecorum 25-3T, with demonstrated safety in in vitro as well as in animal models. Here, we examined the strain's safety, tolerability, and impact on microbiota composition and metabolic activity in healthy volunteers in a randomized, double blind, placebo-controlled, crossover study in 30 healthy volunteers. Study design consisted of two four-week intervention periods (108 CFU B. pullicaecorum [treatment] or maltodextrin [placebo] per day) with a three-week washout in between. We assessed adverse events, blood parameters (primary endpoints), and fecal microbiota composition and metabolite profiles (secondary endpoints).The number of reported adverse events during the B. pullicaecorum treatment was similar to placebo intervention, as were observed changes in blood chemistry parameters, bowel habits, and fecal calprotectin concentrations. Administration of the strain did not induce any disruptive effect in microbiota composition or metabolic activity. In this first human intervention trial with a butyrate-producing Clostridium cluster IV isolate, we demonstrated B. pullicaecorum 25-3T administration to be both safe and well tolerated by healthy participants. This safety study paves the way for the further development of the strain as a next-generation probiotic.

  Study EGAS00001003276

• Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

  We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 µm sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-naïve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

  Study phs003865

• Molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (N2M2/NOA-20 phase I/IIa umbrella trial)

  Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N2M2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients.

  Study EGAS00001008033

• sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids

  We developed conditions to model conditions of diastolic dysfunction caused by inflammatory factors in human cardiac organoids. Our organoid model is based on conditions promoting maturation (Mills et al., PNAS, 2017 and Voges et al., In Revision) and incorporating human pluripotent stem cell derived cardiomyocytes, epicardial cells, fibroblasts, endothelial cells and pericytes. Following 15 days of differentiation (Voges et al., Development, 2017) we formed human cardiac organoids incorporating both our multicellular differentiation (Mills et al., PNAS, 2017) and additional endothelial cells (Voges et al., In Revision). After another 12 days of maturation in 5 days maturation medium and 5 days weaning medium (Voges et al., In Revision) human cardiac organoids were either treated with weaning medium or “cardiac cytokine storm” comprised of 100 ng/ml IFNg, 10 ng/ml IL-1 β and 10 µg/ml poly(I:C). After 48 hours human cardiac organoids were harvested and snap frozen in -80C before nuclei isolation and single nuclei RNA sequencing.Pooled hCO (~40) were homogenized in 4 mL lysis buffer (300 mM sucrose, 10 mM Tris-HCl (pH = 8), 5 mM CaCl2, 5 mM magnesium acetate, 2 mM EDTA, 0.5 mM EGTA, 1 mM DTT)(all Sigma-Aldrich) with 30 strokes of a dounce tissue grinder (Wheaton). Large pieces of hCO were allowed to settle and homogenate was passed through pre-wetted 40 µm cell strainers (Becton Dickinson). Remaining hCO material in the douncer was resuspended in 4 mL and the douncing and filtering steps were repeated twice. All steps of the homogenization were performed on ice. The filtered homogenate was centrifuged at 1500 x g for 5 min at 4oC. Nuclei pellets were then re-suspended in PBS. A fraction of resuspended nuclei were then stained with hoechst nuclear stain (1:500 dilution) and counted on a haemocytometer under fluorescent microscope.The nuclei were then re-centrifuged (1500 x g for 5 min at 4°C) and resuspended at a density to load ~5,000 nuclei per sample. Cell were loaded into the Chromium Controller (10X Genomics) for gel bead emulsion (GEM) formation. Library preparation was conducted according to the manufacturer’s recommended protocol using the Chromium Next GEM Single Cell 3’ GEM, Library & Gel Bead Kit v3.1. Libraries were sequenced on the NextSeq 500/550 v2 (Illumina) with 150 bp reads.In the snRNA-seq we note the lower than expected percentage of non-myocytes and the loss of endothelial cells (Mills et al., PNAS, 2017 and Voges et al., In Revision), indicating the protocol requires further optimization for hCO samples.

  Study EGAS00001005174

• Efficacy of two different FGFR-inhibitors in a patient with extrahepatic cholangiocarcinoma harboring an FGFR2 mutation

  Cholangiocarcinomas (CCAs) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the FGFR family of receptor tyrosine kinases. These drugs are effective and have been approved for cholangiocarcinomas with fusions or rearrangements of FGFR genes. In contrast, the role of these inhibitors in cholangiocarcinomas with mutations in FGFR genes is less well defined. We report here a patient with a cholangiocarcinoma bearing a FGFR2 p.Ser252Trp mutation. The patient was treated with two different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefit from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations. This is the first case to report the clinical benefit of these drugs in FGFR2 p.Ser252Trp mutation. Clinical benefit can be sustained, as seen in our patient. Our case also shows that FGFR inhibitors-induced adverse effects, such as ocular toxicities, may not recur after re-challenge with an alternative drug of the same class.

  Study EGAS50000000015

• The Role of CTCF in the Organization of the Centromeric 11p15 Imprinted Domain Interactome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder and comprises a spectrum of overgrowth phenotypes. While approximately 35% of BWS cases are caused by isolated loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15, only around 5% of patients develop BWS due to structural alterations to the IC2 domain. In this study, we identify a BWS-causing 7.6 kB familial deletion within the IC2 domain by performing Whole Genome Sequencing (WGS) on patient-derived human fibroblasts. Using a chromatin conformation capture technique, Capture C, on 3 control fibroblast samples, 3 BWS LOM fibroblast samples, and the single familial deletion sample, we investigate how the domain interactome changes in BWS patients. We find that high-strength interactions occur within the IC2 domain between the 5’ end of KCNQ1, KCNQ1 intron 2, and the 5’ end of CDKN1C in the control profile that are largely abrogated in the BWS samples, but some lower frequency contacts between the imprinting control region (ICR), KCNQ1 intron 2, and the 5’ end of CDKN1C are unaffected. We conclude that the strong KCNQ1-CDKN1C interactions are important in maintaining the domain imprint.

  Study phs002408

• Whole Transcriptome Sequencing of Human Tumor Cells and Hematopoietic Stem and Progenitor Cells During Aging and Bone Marrow Disorders

  Whole transcriptome sequencing analyses were performed on human hematopoietic stem and progenitor cells during aging and bone marrow disorders. For this purpose, normal and diseased bone marrow or peripheral blood-derived mononuclear cells were FACS-purified into hematopoietic stem (CD34+CD38-Lin-) or hematopoietic progenitor (CD34+CD38+Lin-) populations. Primary human samples from healthy individuals were used along with comparative analyses in some pre-malignant and malignant conditions, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and plasma cell dyscrasias (e.g., multiple myeloma). Studies were also performed on total mononuclear cell fractions from patients with newly-diagnosed or relapsed multiple myeloma, or plasma cell leukemia. Briefly, RNA was extracted from all samples and quality was assessed using a Bioanalyzer instrument. Only samples with RNA integrity (RIN) values >7 were subjected to library preparation for RNA-sequencing. The SMARTer v4 cDNA amplification kit was used along with library construction by the NEB Ultra DNA kit for Illumina. Paired-end sequencing was performed on Illumina NextSeq instruments (Scripps Next Generation Sequencing Core), with all samples run over two separate flow-cells (to generate additional sequencing reads); >95M reads were generated in total for each sample. The RNA-sequencing data are available as FASTQ files.

  Study phs002291

• Germ Cell and Associated Heme Malignancies Evolve from a Common Shared Precursor

  Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15-40. While most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal non-seminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggests a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals has not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of fifteen patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced TP53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor which gives rise to the parallel evolution of GCTs and blood cancers in these patients. Reprinted from PMID: 32897884, with permission from JCI.

  Study phs002231

• CIP: Obesity-Diabetes Familial Risk, Viva La Familia Study

  The VIVA LA FAMILIA Study was designed to identify genetic variants influencing childhood obesity and its comorbidities in the Hispanic population. Family recruitment and phenotyping were conducted in 2000-2005 in Houston, TX. All enrolled children (n=1030) and parents gave written informed consent or assent. The protocol was approved by the Institutional Review Boards for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals and for Texas Biomedical Research Institute. The VIVA LA FAMILIA study design and methodology have been described in detail (Butte NF, 2006). Each family was ascertained on an obese proband, defined as a BMI > 95th percentile, between the ages 4-19 y. The cross-sectional, longitudinal study design consisted of baseline measurements, with a one-year. GWAS was performed using the Illumina HumanOmni1 v1.0 BeadChips on 815 children from 263 Hispanic families and HumanOmni 2.5-8v1 on an additional 43 children. Exome sequencing is being performed on 822 children using NimbleGen capture, followed by Illumina DNA sequencing. Butte NF, Cai G, Cole SA, Comuzzie AG. Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in Hispanic population. Am J Clin Nutr 2006;84(3):646-54. PMID: 16960181

  Study phs000616

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• Study of the Human Skin Metagenome Associated with Acne

  Studies have emphasized the importance of disease-associated microorganisms in perturbed communities, however, the protective roles of commensals are largely under recognized and poorly understood. Using acne as a model disease, we investigated the determinants of the overall virulence property of the skin microbiota when disease- and health-associated organisms coexist in the community. By ultra-deep metagenomic shotgun sequencing, we revealed higher relative abundances of propionibacteria and Propionibacterium acnes phage in healthy skin. In acne patients, the microbiome composition at the species level and at P. acnes strain level was more diverse than in healthy individuals, with enriched virulence-associated factors and reduced abundance of metabolic synthesis genes. Based on the abundance profiles of the metagenomic elements, we constructed a quantitative prediction model, which classified the clinical states of the host skin with high accuracy in both our study cohort (85%) and an independent sample set (86%). Our results suggest that the balance between metagenomic elements, not the mere presence of disease-associated strains, shapes the overall virulence property of the skin microbiota. This study provides new insights into the microbial mechanism of acne pathogenesis and suggests probiotic and phage therapies as potential acne treatments to modulate the skin microbiota and to maintain skin health.

  Study phs001655

• Longitudinal Study of Urea Cycle Disorders

  Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. The purpose of this study is to conduct a longitudinal investigation of the natural history, morbidity, and mortality in people with UCD. This study will look at how people with a UCD grow and develop over time and how often they get sick. The research questions are: What is the prevalence of specific morbid indicators of disease severity, including hyperammonemia, developmental disabilities, and various long-term kidney and liver effects? What is the fatality rate associated with the various forms of UCD? What are the correlations between various biomarkers and disease severity and progression? What is the safety and efficacy of currently used and new UCD therapies? This is a longitudinal study of individuals with urea cycle disorders. Those participating in this study will be evaluated every three to twelve months, depending age and time of diagnosis. Participants two years of age and younger that were diagnosed with UCD within the first four weeks of life will be evaluated every three months. Those who are over two years of age or were diagnosed after four weeks of age will be evaluated every six months. Participants older than 18 years of age will be evaluated once every year.

  Study phs000577

• Genomic Studies of Gilles de la Tourette Syndrome

  This study consists of three components. The first component includes genome-wide association study (GWAS) data on 695 TS cases and 198 ancestry matched controls from the first TS GWAS of 1285 TS cases and 4964 ancestry matched controls. The second component includes genome-wide association study (GWAS) data on 2106 TS cases from the second TS GWAS of 2716 TS cases and 3762 ancestry matched controls. The third component consists of 438 individuals representing 146 probands with DSM-IV-TR diagnosed Tourette Syndrome and their parents (146 complete parent-offspring trios). These individuals are part of the whole exome sequencing study, aiming to use whole exome sequencing of TS parent-offspring to identify de novo protein-truncating variants (PTVs) that are present in the child with TS but not in either parent. All subjects were collected by the Tourette Association of America International Consortium for Genetics (TAAICG) at seven sites in the United States and Canada. Both affected individuals and unaffected relatives were assessed for the presence of Tourette Syndrome and Chronic (Persistent) Tic Disorder (CTD) using a standardized, semi-structured interview, which has high clinical validity and reliability for the diagnoses of TS and CTD (TSAICG, Am J Hum Genet, 2007 (PMID: 17304708)); Darrow et al., Psychiatric Research, 2015 (PMID: 26054936)).

  Study phs001380