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• ICU_transcriptomics__Assessing_the_role_of_the_host_immune_response_in_patients_with_ventilator_associated_pneumonia

  The aim of the proposed project is to provide transcriptomic sequencing data analysis of cells isolated from bronchioalveolar lavage and blood samples from critically ill patients with pneumonia on an intensive care unit in order to investigate the host contribution to disease. The lung microbiome of these patients will be analysed in parallel by deep sequencing and 16S sequencing. These data will provide important information to the development of strategies aimed at improving patient outcomes, reducing the development of antimicrobial resistance and facilitating infection control measures in hospital. Specifically, the proposed work will be a proof of principle study of 100 patients. We will use transcriptomic data to define the host contribution to the symptoms of these critically ill patients diagnosed with pneumonia. The data will be correlated with cytokine/chemokine concentrations, routine microbiology analysis and pathogen genomic data from the same samples to determine the ecology of the lungs of these patients. We will look for associations between clinical features, host response and pathogen genomics in order to identify new diagnostic markers. This study should provide important information to improve the speed and accuracy of diagnosis - resulting in more targeted and successful treatment of critically ill patients in the ICU. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003074

• Genomic analysis of head and neck squamous cell carcinoma upon acquired resistance to cetuximab

  Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab) remain the only FDA-approved targeted therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Unfortunately, most patients develop acquired resistance to cetuximab and there is currently no further therapeutic option for these patients (unmet clinical need), thereby highlighting the need to better understand resistance-causing mechanisms. Here, we carried out whole-exome sequencing on 2 cetuximab-sensitive and -resistant patient-derived xenograft models of HNSCC. Our data reveal several genetic alterations (mutations and copy number variations) associated with acquired resistance to anti-EGFR therapy.

  Study EGAS50000000800

• IMPRESS_all

  Dataset containing tumor, normal and blood sample data, for various tissue and tumor types. Data is targeted methylation data, using smMIP probes to target informative CpG sites in the genome. Sample type can be inferred from the name, with 'W' being normal samples and 'TC' tumor samples. Dataset contains 259 samples in duplicate, with one half of the runs being cut by MSRE's, and the other not. For every sample paired fastq files are present.

  Dataset EGAD50000000882

• TCS validation of 11 lung adenos

  This is the targeted capture deep sequencing (TCS) data for validation of the mutations discovered in the WES step. There are 58 bam files of TCS data including 48 tumor samples and 10 peripheral blood WBC samples.

  Dataset EGAD00001000985

• Genome-Wide Environment Interaction Study on Neurodevelopment in Children from Mexico and Bangladesh

  Cognitive development is known to be highly heritable, but various genome wide association studies (GWAS) have failed to find common single nucleotide polymorphisms (SNPs) which can explain a large proportion of the variance in cognitive ability. We hypothesized that an interaction between genes and exposure to potentially toxic metals may account for some proportion of this missing heritability. We genotyped 749 infants in Mexico and 636 infants in Bangladesh. Criteria for inclusion into the study are given below. We then performed a Genome Wide Environmental Interaction Study (GWEIS) with neurodevelopment outcomes. There were 552,487 SNPs in common between the two cohorts.

  Study phs000996

• The exomic landscape of t(14,18) negative diffuse follicular lymphoma with 1p36 deletion

  t(14,18) negative diffuse follicular lymphoma with 1p36 deletion is a well characterized variant of follicular lymphoma with typical clinical, morphological, immunophenotypical and genetic features. The genetic landscape of this variant is however largely unknown. We performed exome sequencing of six well characterised cases and detected 1642 single nucleotide variations and 641 insertions-deletions not reported in common databases (dbSNP and 1000G). We report several recurrent mutations, among which CREBBP, STAT6, KMT2D, HEATR6, LAMA5 and VPS13B are the most prevalent. Pathway annotation using GSEA showed an enrichment in mutated genes belonging to the MAPK pathway.

  Study EGAS00001002594

• Phylogenetic Analyses of Melanoma Reveal Complex Patterns of Metastatic Dissemination

  Subpopulations of cells in a primary melanoma can disseminate and establish metastases. Still, the precise ancestral relationship between primary tumors and their metastases is not well understood. Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of 8 patients to determine their phylogenetic relationships, profiling a total of 31 total tumors. The resulting data show that in 6 of 8 cases, genetically unique cell populations in the primary metastasized in parallel to distinct anatomic sites, rather than sequentially. These data also indicate that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct.

  Study phs000941

• ROBUST (NCT02285062)

  The ROBUST clinical trial is a Phase III, randomized, double-blind, placebo-controlled study designed to compare the efficacy and safety of lenalidomide plus R-CHOP chemotherapy (R2-CHOP) versus placebo plus R-CHOP in newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Molecular data was collected for all patients at screening, but the only patients of the Activated B-cell (ABC) cell-of-origin subtype were eligible for study inclusion and clinical follow-up. We have performed unsupervised clustering on this cohort and identified 7 novel transcriptional subtypes of DLBCL, one of which represents a high-risk subset of patients with high MYC expression, ABC-associated biology, and low immune infiltration.

  Study EGAS50000000333

• Genetic landscape of pediatric Medulloblastoma

  Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.

  Study EGAS00001000347

• Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

  Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for WGS. New bioinformatic methods have been developed to take advantage of this long read data, however much of the validation of these tools has focussed on calling germline variants (both SNVs and structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated due to their frequency varying depending on tumour purity/subclonality. Here, we evaluate the extent to which Nanopore WGS enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma. We examine the capability of currently available tools for calling somatic variants in ONT data by comparing the data with results from 150bp short-read sequencing of the same samples. We then conduct a detailed analysis of the performance of multiple long-read mappers and structural variant callers for calling large, somatic structural variants (SVs) in ONT data. Our protocol achieved yields of up to 96 mapped Gb per PromethION flow cell with average read lengths of ~5kb. Calling germline SNVs from these data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. Our analysis of structural variants shows that the comparative performance of different tools varies significantly between SV types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants by using the ONT data to confirm that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

  Study EGAS00001004266