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• Sequencing_Acute_Myeloid_Leukaemia_

  This project will aim at sequencing and analysing three samples from a patient with acute myeloid leukaemia (AML) with t(15;17) translocation (acute promyelocytic leukaemia). The patient was treated with standard chemotherapy and samples (blood and bone marrow) taken for minimal residual disease measured during and after chemotherapy. 2-3years later the patient presented a second AML containing inv (16).In this project we will sequence both AML and normal genomes to find associated mutations This will allow unprecedented insights into the dynamics of appearance of secondary AML, since we will be able to use the MRD samples to track the emergence of the inv(16) leukaemia. We will also be able to distinguish whether the 2 leukaemias are clonally related or not. This project will entail sequencing and analysis of three samples (whole genome 30x coverage) using Hi-Seq. The funds from this grant will cover the cost of sequencing 9 lanes from the AML t(15;17) sample, 9 lanes from AML inv(16) sample and 8 lanes from the normal genome.

  Study EGAS00001000035

• Long-read mRNA sequencing of retinal organoids

  Long-read (PacBio) sequencing of two retinal organoid samples. One sample was treated with cyclohexamide. Files are ccs BAM format files generated by a Sequel IIe machine.

  Dataset EGAD50000000100

• WGS FASTQ files studied in A first-in-human clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy

  This data set contains 2 paired fastq files (WGS).

  Dataset EGAD50000000947

• Whole genome sequencing of osteosarcoma and blood

  We profiled 2 patient osteosarcoma tumor samples as well as the blood of the same patients by whole genome sequencing, for a total of 4 samples. The raw fastqs are provided.

  Dataset EGAD00001011372

• Mechanism and Response of Thymoglobulin in Patients with Myelodysplastic Syndrome (MDS)

  In people with MDS, the bone marrow stops making healthy blood cells and instead produces poorly functioning, malformed, and immature blood cells. This can lead to anemia resulting from too few healthy red blood cells, infection resulting from too few healthy white blood cells, and bleeding resulting from too few healthy platelets. The exact cause of MDS remains unknown, but it may be caused by abnormal autoimmune activity in which activated T cells, a type of white blood cell, prevent normal bone marrow production. ATG, a medication that inhibits immune function, can restore normal blood production in some people with MDS, but it is not known how this happens and why it does not happen in all MDS patients. The purpose of this study is to examine the effects of ATG in adults with MDS and to determine which individuals with MDS are most likely to benefit from treatment with ATG. Based on disease severity and likely disease progression, participants will be separated into either a high-risk group or a low-risk group. Participants will be hospitalized for a 4-day period during which they will receive daily infusions of ATG. Oral prednisone will be given 2 days before hospitalization, throughout hospitalization, and then for 14 days after hospitalization to limit the side effects of ATG. Antihistamines and acetaminophen will also be given during hospitalization to reduce the chances of an allergic reaction to ATG. After discharge, all participants will attend monthly study visits that will include blood collection, review of disease symptoms, and evaluation of medication response. At Week 16, participants in the high-risk group will undergo additional blood collection, a bone marrow biopsy, and a thorough evaluation of disease progression and the effects of MDS on daily living abilities. Participants in the low-risk group will undergo these same procedures at Week 24. Follow-up for all participants may last up to 2 years.

  Study phs000697

• Whole-genome and transcriptome versus panel sequencing in precision oncology: A translational-clinical comparison

  Precision oncology offers new cancer treatment options. While the use of whole-genome (WGS) and transcriptome (TS) sequencing remains often confined to specific clinical programs, molecular analysis with gene panels is more common clinical practice. Methods: Twenty patients with rare or advanced tumors sequenced by WGS/TS within the DKFZ/NCT/DKTK-MASTER program from 2015 to 2020 (MASTER 1) were additionally sequenced with the TSO500 DNA and TST170 RNA Assay by Illumina. Original Molecular Tumor Board (MTB) therapy recommendations (TR) were juxtaposed with TR from NGS panel data analysis (comparison 1). To mitigate temporal differences between the two sequencings, WGS/TS was bioinformatically reanalyzed (MASTER 2), and new TR were again compared (comparison 2). Results: In comparison 1, 47.1% of the MASTER 1’s TR and 62.8% of the panel’s TR were identical, as were 45.9% of the TR of MASTER 2 and 54.9% of the panel in comparison 2. In both MASTER 1 and MASTER 2, 26.5% and 36.1% of TR, respectively, relied on Biomarkers (BM) which were not covered by the panel. Eight of the ten MTB-derived therapy implementations were also supported in the panel, the two remaining ones being based on BM absent from the panel. Conclusions: About half of the TR in WGS/TS and panel sequencing were identical. Around a third of TR issued by WGS/TS were based on BM which are not covered by the panel, leading to therapy implementations. The presented data underscores the clinical value of comprehensive molecular analyses in individuals with advanced cancers.

  Study EGAS50000000431

• RNAseq dataset for MALT1 in MCL

  Manuscript Title: Co-targeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma Journal: Journal of Clinical Investigation Authors Vivian Changying Jiang1, Yang Liu1, Junwei Lian1, Shengjian Huang1, Alexa Jordan1, Qingsong Cai1, Fangfang Yan3, Joseph Mitchell McIntosh1, Yijing Li1, Yuxuan Che1, Zhihong Chen1, Jovanny Vargas1, Maria Badillo1, JohnNelson Bigcal1, Heng-Huan Lee1, Wei Wang1, Yixin Yao1, Lei Nie1, Christopher Flowers1, and Michael Wang1, 2* Abstract Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11 knockout cells showed anti-tumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK-CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K-ATK-mTOR, and integrin signaling. Importantly, co-targeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and co-targeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes. Dataset description: The bulk RNA-seq dataset was generated for the cell lines below and used for two major purposes: 1. DEG analysis and GSEA analysis comparing IBN-R and IBN-S cells 2. DEG analysis and GSEA analysis comparing MCL cells with/without MI-2 treatment. sample Cell MI-2 Ibrutinib (IBN) Venetoclax (VEN) Used for IBN-R vs IBN-S comparison Used for MI-2 vs untreated (DMSO) H9 Granta519 - R S yes H21 Granta519 - R S yes H33 Granta519 - R S yes H10 Granta519-VEN-R - R R yes H22 Granta519-VEN-R - R R yes H34 Granta519-VEN-R - R R yes H3 JeKo BTK KD_1 - R R yes yes H15 JeKo BTK KD_1 - R R yes yes H27 JeKo BTK KD_1 - R R yes yes H5 JeKo BTK KD_2 - R R yes yes H17 JeKo BTK KD_2 - R R yes yes H29 JeKo BTK KD_2 - R R yes yes H1 JeKo-1 - S R yes yes H13 JeKo-1 - S R yes yes H25 JeKo-1 - S R yes yes H7 Mino - S S yes H19 Mino - S S yes H31 Mino - S S yes H8 Mino-VEN-R - S R yes H20 Mino-VEN-R - S R yes H32 Mino-VEN-R - S R yes H11 Rec-1 - S S yes H23 Rec-1 - S S yes H12 Rec-VEN-R - S S yes H24 Rec-VEN-R - S R yes H36 Rec-VEN-R - S R yes H35 Rec-1 -- S R yes H4 JeKo BTK KD_1 + MI-2 + yes H16 JeKo BTK KD_1 + MI-2 + yes H28 JeKo BTK KD_1 + MI-2 + yes H6 JeKo BTK KD_2 + MI-2 + yes H18 JeKo BTK KD_2 + MI-2 + yes H30 JeKo BTK KD_2 + MI-2 + yes H2 JeKo-1 + MI-2 + yes H14 JeKo-1 + MI-2 + yes H26 JeKo-1 + MI-2 + yes

  Dataset EGAD00001009771

• Transcriptome sequencing of neuroendocrine tumors of the small intestine

  This dataset contains 206 RNASeq samples from a cohort of patients with neuroendocrine tumors of the small intestine. Libraries were prepared using a Illumina TruSeq Stranded mRNA kit following the manufacturer’s recommendations. Sequencing was performed on Illumina Novaseq6000 machine with a 2x75bp paired-end fashion. This dataset contains data for 169 tumors, 22 mesenteric nodules, 8 liver metastases, 2 adenomas, 1 lymph node and 4 normal ileum samples.

  Dataset EGAD50000000906

• Ultra-deep sequencing of cell-free DNA derived from reference materials and a patient with asymmetric overgrowth

  This dataset contains: Ultra-deep sequencing data using the Duplex sequencing technology of: 1.) SeraSeq cfDNA reference materials with spike-in variants with allele frequencies from 0% to 5% 2.) One cfDNA sample from a CRC patient 3.) One cfDNA sample from a patient with asymmetric overgrowth Paired-end sequencing was performed with 2x151 bp reads on the NextSeq 500 system. Data is provided as mapped .bam files (aligned to GRCh38/hg38).

  Dataset EGAD00001009784

• RNASeq_EGAS00001001306

  RNASeq sequencing. Each library was sequenced using TruSeq SBS Kit v3-HS, in paired-end mode with a read length of 2 × 76 bp. We generated more than 20 million paired-end reads for each sample in a fraction of a sequencing lane on HiSeq2000 (Illumina Inc.) following the manufacturer’s protocol. Image analysis, base calling and quality scoring of the run were processed using the manufacturer’s software Real Time Analysis (RTA 1.13.48) and followed by generation of FASTQ sequence files.

  Dataset EGAD00001001443

• Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to the Antibody Drug Conjugate Sacituzumab Govitecan

  Sacituzumab Govitecan (SG), a novel antibody drug conjugate (ADC) incorporating the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 inhibitor (SN-38) payload, is the first ADC to be approved for advanced triple negative breast cancer (TNBC). However, mechanisms governing therapeutic resistance to SG are not known. We sought to identify mechanisms of de novo and acquired resistance to SG through unbiased whole-exome sequencing (WES) and RNA sequencing analysis of pre-treatment and multi-site post-progression (autopsy) tumor specimens. We examined three metastatic TNBC cases exhibiting (1) de novo progression, (2) stable disease, and (3) a deep response followed by progression, then mapped the temporal and spatial genomic evolution of acquired resistance in the responding patient. We then conducted additional pre-clinical experiments to validate the observed resistance mechanisms. TROP2 RNA and gene copy number were associated with de novo resistance, as case (1) was found to have absent TROP2 expression in all specimens, case (2) expressed TROP2, while case (3) exhibited both expression and focal genomic amplification of the TACSTD2/TROP2 locus. The genomic phylogeny tree inferred from case (3) post-progression specimens revealed one branch harboring an acquired canonical E418K resistance mutation in TOP1 (encoding topoisomerase 1) and a subsequent sub-clonal TOP1 inactivating frameshift mutation, while a distinct branch exhibited acquisition of a novel T256R missense mutation in TACSTD2 (encoding TROP2). Both the TOP1- and TACSTD2-mutant clones seeded multiple distinct metastatic sites. Through reconstitution experiments in TROP2 negative cells we found that TROP2 T256R is a stable protein with defective cell membrane localization and reduced cell surface binding by RS7 compared to wild-type TROP2. Collectively, these findings underscore TROP2 as a determinant of initial response to SG, and they reveal parallel and mutually exclusive polyclonal molecular mechanisms of acquired resistance involving the direct antibody target and drug payload target in distinct metastatic subclones of a single patient. While further research is needed to extend these novel findings, this study highlights the specificity of SG and illustrates how identifying such mechanisms will inform rational therapeutic strategies to overcome ADC resistance.  

  Study phs002555

• PGRN/PAT: The genomic basis for susceptibility to drug-induced long QT syndrome (diLQTS)

  The goal of this study was to search for genetic variants that could be responsible for modifying the risk of drug-induced long QT syndrome (diLQTS). diLQTS is a relatively common adverse drug event and has been a leading cause for drug relabeling and withdrawal from the market. Our hypothesis, that variants in genes which regulate electrical properties in the heart modify the risk of diLQTS, was tested by sequencing approximately 225 patients of European descent using next-generation targeted captured or whole exome sequencing. Data from cases and controls (1:2) were analyzed to identify both rare and common genetic variation.

  Study phs000808

• Genetic Basis of Cryptorchidism

  Non-syndromic cryptorchidism is a common malformation, but the genetic loci that increase susceptibility to cryptorchidism remain unknown. A genome-wide association study (GWAS) was completed to determine whether common allelic variants are associated with susceptibility to cryptorchidism. Two sets of discovery groups were genotyped. Group 1 (559 cases and 1772 controls) was genotyped with HumanHap550v1.0, HumanHap550v3.0 or Human610-quad v1.0. Group 2 (353 cases and 1149 controls) was genotyped with HumanOmniExpress-12v1 or HumanOmniExpress-12v1-1. The sample and marker QCs were performed separately using PLINK (v1.07; http://pngu.mgh.harvard.edu/purcell/plink/) and logistic regression analyses were performed with first and second multidimensional scaling (MDS) components as covariates.

  Study phs000986

• Understanding Rare Variant Contributions to autism: Lessons from Dystrofin-Deficient Model

  This project generated a whole-exome sequencing (WES) dataset of 83 boys with a pathogenic variant in the DMD gene, along with WES data from the parents of 38 of them, totaling 159 samples. Pathogenic DMD variants, besides causing dystrophinopathies, are also known risk factors for neurodevelopmental disorders (NDDs). However, the low penetrance of NDDs in individuals with dystrophinopathies suggests that additional factors contribute to their manifestation. This study aimed to: (1) characterize ASD in males with dystrophinopathies; (2) determine the relevance of additional de novo and inherited rare risk variants for their neurodevelopmental phenotype; and (3) clinically and functionally characterize the identified risk variants.

  Study EGAS50000000754

• GOSH_Paediatric_Tumour_23P108_WSSS_WGS_Managed_Access

  We have a case of two siblings (twins) who were born with nodular blue rashes over their body. The first twin had a large periorbital subcutaneous mass which was diagnosed as infantile undifferentiated sarcoma. This baby was too systematically unwell for chemotherapy and died at 12 days of age. The second sibling received two cycles of emergency chemotherapy however died due to disease progression and secondary haemorrhage at 2 months of age. Post-mortem normal and tumour samples have been taken. In addition to placental tissue and parental germline DNA, the goal will be to investigate intra-uterine transfer of sarcoma and the phylogenetic relationship of tumours in both twins.

  Study EGAS00001007536

• Mutational signatures in head and neck cancer (H019)

  Genomic alterations are a driving force in the multistep process of head and neck cancer (HNC) and result from the interaction of exogenous environmental exposures and endogenous cellular processes. Each of these processes leaves a characteristic pattern of mutations on the tumor genome providing the unique opportunity to decipher specific signatures of mutational processes operative during HNC pathogenesis and to address their prognostic value. Computational analysis of whole exome sequencing data of the HIPO-HNC (n=83) and TCGA-HNSC (n=506) cohorts revealed five common mutational signatures (COSMIC signature 1, 2, 3, 13 and 16), and demonstrated their significant association with etiological risk factors (tobacco, alcohol and HPV16).

  Study EGAS00001004588

• Fecal microbiota transplantation - Effect of engraftment on plasma metabolomics and cllinical outcomes

  Fecal Microbiota Transplantation (FMT) has emerged as a potential modality for mitigating microbiome-associated diseases. Despite this potential, the precise causal pathways by which specific gut microbiota strains induce remission remain inadequately elucidated. In this study, we aimed to discern the impact of engraftment of donor-infused strains on alterations in plasma metabolites, subsequently contributing to the amelioration of clinical parameters involved in subjects with metabolic syndrome (MetSyn) receiving an FMT. We observed that a higher fraction of donor strains engrafted in the recipient is correlated to a reduction in diastolic blood pressure and found specific strains associations through Canonical correlation analysis. Integrating the metabolomics profile show that engraftment of Collinsella aerofaciens and Fusocatenibacter saccharovorans was related to a reduction in 2 oxoarginine in plasma, which was subsequently correlated to a reduction in diastolic blood pressure. In conclusion, we applied a novel framework to elucidate on the complex and heterogenous FMT intervention, establishing a connection between engrafted microbiota and clinical outcome parameters. Our findings underscore the potential therapeutic efficacy of FMT in ameliorating MetSyn, demonstrating a potential contribution of microbial strain engraftment to the improvement of MetSyn via modulation of circulating metabolites.

  Study EGAS50000000409

• H3K27ac ChIP-seq in a selected group of AML patients

  ChIP-seq data were generated for a number of selected patients to investigate changes in enhancer and promoter regions. ChIP was performed as described previously with slight modifications27. Briefly, cells were crosslinked with 1% formaldehyde for 10 minutes at room temperature and the reaction was quenched with glycine at a final concentration of 0.125 M. Chromatin was sheared using the Covaris S220 focused-ultrasonicator to an average size of 250–350 bp. A total of 2.5 µg of antibody against H3K27ac (Abcam, ab4729) was added to sonicated chromatin of 2 × 106 cells and incubated overnight at 4 °C. Protein A sepharose beads (GE healthcare) were added to the ChIP reactions and incubated for 2 h at 4 °C. Beads were washed and chromatin was eluted. After crosslink reversal, RNase A and proteinase K treatment, DNA was extracted with the Monarch PCR & DNA Cleanup kit (NEB). Sequencing libraries were prepared with the NEBNext Ultra II DNA Library Prep Kit for Illumina (NEB) according to the manufacturer’s instructions. The quality of dsDNA libraries was analyzed using the High Sensitivity D1000 ScreenTape Kit (Agilent) and concentrations were assessed with the Qubit dsDNA HS Kit (Thermo Fisher Scientific). Libraries were single-end sequenced on a HiSeq 4000 (Illumina). ChIP-seq reads were aligned to the human reference genome build hg19 with bowtie

  Dataset EGAD00001007582

• SARS-CoV-2 host genetics and COVID-19 outcomes in admixed Brazilians with extreme phenotypes

  COVID-19 comprises clinical outcomes of SARS-CoV-2 infection and is highly heterogeneous, ranging from asymptomatic individuals to deceased young adults without comorbidities. There is growing evidence that host genetics play an important role in COVID-19 severity, including inborn errors of immunity, age-related inflammation and immunosenescence. This study proposes a strategy of subject’s ascertainment based on phenotypic extremes to take part in genomic studies and elucidate intrinsic risk factors involved in COVID-19 severe outcomes. Different cohorts were collected and submitted to Next-Generation Sequencing (Whole exome and whole genome sequencing).

  Study EGAS00001006376

• A spatiotemporal organ-wide gene expression and cell atlas of the developing human heart

  Dataset includes 2 scRNA-seq samples from a 6.5-7 post-conception weeks human embryonic heart and 19 samples from 4.5-9 post-conception weeks human embryonic hearts analyzed with the Spatial Transcriptomics method. H&E stains can be sent if requested.

  Dataset EGAD00001005468

• Epigenomic analysis of human dopaminergic neuron differentiation reveals LBX1, NHLH1 and NR2F1/2 as necessary for lineage specification

  Sample information: The 56 samples produced in this project come from the human iPSC line GM17602 (Coriell) where a tyrosine hydroxylase-T2A-mCherry reporter was inserted. A combination of epigenetic analysis (ATAC/ChIP) along transcriptomics.

  Dataset EGAD00001009288

• Somatic Mutations in 3,929 HPV-Positive Exfoliated Cervical Cell Samples

  We investigated the detection, timing, and HPV type specificity of cervical somatic hotspot mutations (i.e., previously reported cancer driver mutations) in 3,929 HPV-positive exfoliated cervical cell samples from individuals undergoing routine cervical screening in the U.S. using deep-targeted sequencing of 20 candidate genes. Our study included samples from 3,351 women with the following infection outcomes: 1,478 HPV16-, HPV18- and/or HPV45-positive controls (i.e., HPV infections that did not progress to precancer and/or subsequently cleared), 1,712 cervical precancers, and 161 invasive cervical cancers. We utilized residual exfoliated cervical cell samples from women routinely screened for cervical cancer precursors at Kaiser Permanente Northern California (KPNC) as part of the prospective KPNC-NCI HPV Persistence and Progression (PaP) cohort. We included 3,929 samples collected from these 3,351 women, including 974 serial sample from 396 women collected prior to their most recent screening visit to evaluate somatic hotspot mutation detection prior to diagnosis.

  Study phs003691

• Whole Exome Data for two affected individuals in a family with severe congenital neutropenia (SCN).

  Raw Whole Exome Sequencing data from Blood samples drawn from related Female participants presenting severe congenital neutropenia.

  Dataset EGAD00001005937

• The Oral Microbiome and Head and Neck Cancer

  Oral microbiota may influence head and neck squamous cell carcinoma (HNSCC) development, potentially related to carcinogen metabolism. The human oral cavity hosts a diverse microbiota, including bacteria and fungi. We performed shotgun sequencing and ITS1 sequencing on 236 HNSCC case participants who developed HNSCC during a mean follow-up of 5.1 years and 458 matched controls who remained HNSCC-free. Oral samples were obtained from a prospective nested case-control study within three epidemiological cohorts: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (ACS CPS-II), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Southern Community Cohort Study (SCCS). Control participants were selected using 2:1 frequency matching based on cohort, age, sex, race and ethnicity, and time since oral sample collection.

  Study phs004018

• GCparagon: Evaluation and correction of GC biases in cell-free DNA at the fragment level

  We present GCparagon, a two-stage algorithm for computing and correcting GC biases in cell-free DNA (cfDNA) samples. The length of the highly fragmented cfDNAs and the number of GC bases are essential parameters in the calculations. Regions of low mappability, known reference genome assembly errors and regions surrounding assembly gaps are excluded from the bias computation. GCparagon outputs a bias matrix and an optional tagged BAM file with GC bias balance weights as alignment tags. Parallelization allows calculation of a GC bias estimate in less than 2 minutes per sample with between 99.0% and 99.9% of fragments already corrected. We propose that GCparagon can help standardize cfDNA applications and evaluate the impact of GC bias on algorithms used in the analysis of liquid biopsy data.

  Study EGAS00001006963