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• 13 WGS and 8 TCS data of ENKL patients treated with pembrolizumab.

  Whole-genome sequencing (WGS) was performed for 13 pairs of tumor-normal samples from patients diagnosed with NKTL. Genomic DNA from tumor tissue was extracted with QIAamp DNA Mini Kit. The DNA for the matching normal was obtained from blood or buccal swabs and purified by Blood and Cell Culture DNA Mini kit or E.Z.N.A. Tissue DNA Kit (Omega Bio-tek) according to manufacturer’s instructions. The quantity and quality were assessed by Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen) and agarose gel electrophoresis. All sequencing libraries were prepared using TruSeq Nano DNA Library Prep Kit (Illumina). Paired-end sequencing was performed on Illumina HiSeq 2000 or HiSeq X Ten as 2x101 bp or 2x151 bp, respectively. 8 NKTL FFPE specimens were screened for somatic mutations using deep targeted capture sequencing (TCS). FFPE rolls or slides were extracted using QIAamp DNA FFPE Tissue kit (QIAGEN). The FFPE genomic DNA was treated with NEBNext FFPE DNA Repair Mix and assessed by Quant-it PicoGreen dsDNA Assay Kit (Invitrogen). The library was generated from 10-200 ng DNA with SureSelectXT Low Input Target Enrichment System for Illumina Paired-End Sequencing Library (Agilent Technologies) according to manufacturer’s instructions. RNA based probe was designed with SureDesign (Agilent Technologies) to target-capture 140 genes. Next, the captured libraries were pooled in equimolar concentration and sequenced on Illumina Novaseq 6000 platform with SP or S1 chip. Reads aligning to 40 selected genes were isolated post-alignment for this submission. Prefix used in filenames: T - Tumor samples N - Matched-Normal samples

  Dataset EGAD00001004140

• Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

  Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n=784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

  Study EGAS00001000226

• WES data (cfTrack study) from NSCLC patients and OC patients

  We also collected samples from 8 NSCLC patients and 4 ovarian cancer patients and. For all 8 NSCLC patients, a tumor biopsy sample, a WBC sample, and three plasma samples were collected. For all 4 ovarian cancer patients, a WBC sample and two serum samples were collected. We collected tumor tissue sample from one ovarian cancer patient (OV4). The cfDNA was extracted from their plasma samples using the QIAamp circulating nucleic acid kit from QIAGEN (Germantown, MD). For serum cfDNA, ampure XP beads size selection was further performed to eliminate gDNA contamination. In brief, 0.5 volume of beads were first added to the cfDNA samples. After incubation, the supernatant was transferred to a new tube and an additional 2.0 volume of beads were added. After 80% ethanol wash, cfDNA was eluted from the beads. FA assays (Agilent Technologies) were performed to rule out the contamination of gDNA in the size selected samples. The cfDNA WES library of all patients and the genomic DNA WES library of the 4 ovarian cancer patients were constructed with the SureSelect XT HS kit from Agilent Technologies (Santa Clara, CA) according to the manufacturer’s protocol. In brief, 10ng of cfDNA was used as input material. After end repair/dA-tailing of cfDNA, the adaptor was ligated. The ligation product was purified with Ampure XP beads (Beckman-Coulter, Atlanta, GA) and the adaptor-ligated library was amplified with index primer in 10-cycle PCR. The amplified library was purified again with Ampure XP beads, and the amount of amplified DNA was measured using the Qubit 1xdsDNA HS assay kit (ThermoFisher, Waltham, MA). 700-1000 ng of DNA sample was hybridized to the capture library and pulled down by streptavidin-coated beads. After washing the beads, the DNA library captured on the beads was re-amplified with 10-cycle PCR. The final libraries were purified by Ampure XP beads. The library concentration was measured by Qubit, and the quality was further examined with Agilent Bioanalyzer before the final step of 2x150bp paired-end sequencing at an average coverage of 200. Whole-exome capture libraries of genomic DNA from the 8 NSCLC patients were constructed via Roche SeqCap EZ Exome V6 (Roche). Enriched exome libraries were sequenced on the Illumina HiSeq 3000 platform (Illumina) to generate 2x100bp paired-end reads at an average coverage of 200.

  Dataset EGAD00001008454

• Single-cell RNA-sequencing of CD34+ bone marrow cells from patients with SLE, healthy individuals and umbilical cord blood samples

  All immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult haematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). We reasoned that the fundamental abnormalities in the disease can be traced back to HSPCs. The aim of this study was to delineate human haematopoietic CD34+ progenitor subpopulations and to identify deregulated pathways in each subpopulation in SLE as compared to healthy controls and umbilical cord blood samples. This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors and qualitative differences- characterized by an IFN signature, which is known to drive loss of function and depletion of HSPCs.

  Study EGAS00001007317

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Novel Myeloma Pathobiology Mediators and Potential Targets

  Newly diagnosed symptomatic and relapsed/refractory myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors which have been studied utilizing bulk or single-cell (sc) techniques. By combining scRNA-sequencing with scB-cell receptor (BCR)-sequencing, we found more dysregulated genes in monoclonal PCs compared with analyses of the entire CD138+ population, which includes non-neoplastic/polyclonal PCs. Paired tumor and non-tumor WGS was performed to evaluate the presence of IgH-associated translocations and hyperdiploidy events, initially detected by FISH, in a subset of samples included in this study.

  Study EGAS50000000801

• Genome Wide Association for Asthma and Lung Function

  The SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic (STAMPEED) asthma project includes subjects with asthma and controls from the Chicago Asthma Genetics Study (CAG), NHLBI multicenter Severe Asthma Research Program (SARP) and NHLBI Collaborative Studies on the Genetics of Asthma CSGA (Wake Forest). All studies included European American and African American children and adults with asthma ranging from mild to severe and adult controls. CAG participants were collected at the University of Chicago. SARP participants were recruited at the NHLBI SARP sites with an emphasis on recruiting severe asthmatics (Moore et al, Am J Respir Crit Care Med, 2010, PMID: 19892860). CSGA cases and controls collected by the Wake Forest investigators were also included. Asthma status was based on both a physician's diagnosis and either bronchodilator reversibility or hyper-responsiveness to methacholine as well as less than 5 pack years of smoking. Genotyping was performed on the Illumina 1Mv1 platform, with individual genotypes called using clustering algorithms as implemented in the BeadStudio software by Illumina. The total number of markers following standard QC was 1,025,129. Imputation was performed using the HapMap phase 2, release 21 SNPs using MACH with the phased HapMap CEU and YRI haplotypes as a reference. Case/control association tests for asthma status were performed using logistic regression in R (http://CRAN.R-project.org/) on genotype dosages, and adjusting for the first principal component from EIGENSTRAT.

  Study phs000355

• Low T cell diversity is associated with poor outcome in bladder cancer - Total RNAseq data

  T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed total RNAseq on blood samples from 8 patients with muscle invasive bladder cancer. The goal was to compare blood T cell subtype composition between patients with low and high TCR diversity.

  Study EGAS50000000939

• Investigating the Role of Neddylation in the Repair of Topoisomerase I-Mediated DNA Damage in Colorectal Cancer

  Colorectal cancer is one of the most lethal cancers worldwide. First-line chemotherapy for metastatic CRC (mCRC) entails a combination of irinotecan with 5-fluorouracil and leucovorin (FOLFIRI). Irinotecan is a prodrug that is converted within the cell to its active metabolite SN38, a potent TOP1 inhibitor. TOP1 relieves DNA torsional strain arising from DNA metabolism by cleaving one strand of the DNA duplex and forming an enzyme-DNA covalent intermediate that can be trapped by inhibitors. The resulting TOP1 DNA-protein crosslinks (TOP1-DPCs) interfere with replication and transcription and induce cell death if left unrepaired. I have established the role of the ubiquitin-proteasome pathway in TOP1-DPC repair, but it remains unknown how ubiquitylation is activated. One possibility is that collision between advancing replication forks and the DPCs triggers a specific ubiquitin ligase to target DPCs for degradation. The DDB1-CUL4 (Cullin 4)-RBX1 (CRL4) ubiquitin ligase complex performs a salient role in both replication and DNA repair upon its activation by auto-NEDD8 modification (neddylation), but it is unknown whether it plays a role for TOP1-DPC repair. We plan to define the role of neddylation for TOP1-DPC repair during replication and examine irinotecan plus pevonedistat (PEV), a NEDD8-activating enzyme inhibitor in multiple clinical trials, in CRC patient-derived preclinical models including 3D organoids. The three in-house organoids, from which samples have been submitted to dbGaP, were sequenced as a means of verifying their identity as colon cancer organoids, to allow us to investigate the combination of TOP1 inhibitors and PEV and the molecular mechanisms underlying this drug combination in these organoids.

  Study phs003257

• A single-cell atlas of the early COPD lung

  Single cell atlas of the human airways from 10 patients suffering of early stage Chronic Obstructive Pulmonary Disease and 12 healthy age matched volunteers. This dataset was sequenced by 10X Genomics 3’ RNA-seq profiling. It is composed of more than 400 000 cells coming from 119 samples total. Sampling was performed by brushings and biopsies from the nose to the 6 th division of the airways.

  Dataset EGAD50000001001

• PAK4 inhibition improves PD-1 blockade immunotherapy

  Introduction with rationale and aims for study Immune checkpoint blockade therapies have significantly altered the current landscape of cancer treatment. However, this immunotherapy still fails more often than it succeeds. There are now evidences that the lack of tumour infiltration by immune cells is the main mechanism of primary resistance to PD‐1 blockade therapies for cancer. It has been postulated that cancer cell‐intrinsic mechanisms may actively exclude T cells from tumours, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. With the idea of finding potential drivers of immune exclusion, we performed RNA sequencing analysis of biopsies from melanoma patients and compared the transcriptomic differences of samples that where infiltrated with those that did not have immune infiltration. Methods RNAseq analysis of gene expressions on biopsies from melanoma patients treated with checkpoint blockade were analysed. We focused on the variable of "infiltration: yes or no,", e.g. tumors that were well infiltrated by immune cells with those that kept immune cells out. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors. The kinase PAK4 stood out as a good candidate for inhibition treatment in the future as it was consistently enriched in the samples without immune infiltration. To test whether immunotherapy would work better if we deleted PAK4, we first knocked out PAK4, using CRISPR‐Cas9, in the ‐resistant melanoma cell line, B16. Then they injected the melanoma cells into mice and observed that PAK4 KO tumours now responded to PD‐1 blockade. In order to elucidate whether pharmacological inhibition of PAK4 could recapitulate the results observed in the B16 PAK4 KO tumours, we obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Indeed, inhibiting PAK4 in combination with anti‐PD‐1 immunotherapy significantly slowed the growth of the B16 melanomas more than either drug alone. Results and Conclusions Transcriptomic analysis of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out revealed a list of genes whose expression differed between the infiltrated and non-infiltrated tumours. The result suggests that p21 activated kinase 4 (PAK4) is enriched in non-responding tumour biopsies with low T cell and dendritic cell infiltration. In addition, PAK4 decreased WNT activity, a signalling pathway that has previously been involved in immune exclusion. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD‐1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of with the PAK4 inhibitor, KPT-9274, improved anti‐tumour responses compared to anti‐PD‐1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and lack of response to PD‐1 blockade, which could be reversed with PAK4 inhibition. The data establish a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors for patients. Future work and data that we can anticipate for this study Oncogenic signalling pathways and specially the WNT signalling pathway, have been associated with lack of immune infiltration and resistance to PD‐1 blockade therapies. Here, we show that PAK4 overcome resistance to PD‐1 blockade while significantly decreases WNT signalling activity. Therefore, it constitutes the first potential druggable target that is able to reverse oncogenic driven immune cell exclusion. However, the fully mechanism whereby PAK4 sensitizes tumours to immunotherapy remains to be fully elucidated. It is necessary to address whether PAK4 inhibition overcomes resistance through WNT signalling inhibition or if other signalling pathways are involved in the observed phenotype.

  Study phs001919