16787 results for "sec+and+unspecified+malignant+neoplasm"

in 29.68 milliseconds.

• Nuclease deficiencies alter plasma cell-free DNA methylationprofiles (mouse)

  The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.

  Study EGAS00001004696

• CML_blast_phase_rearrangement_screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from 10 Chronic Myeloid Leukemia in blast phase samples and subjected to a total of two lanes of 50 bp, paired end sequencing on the llumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions

  Study EGAS00001000191

• Paediatric_CNS_tumour_autopsy_DNA

  Investigation of early embryonic mutations can reveal the earliest stages of normal tissue development and the origins of paediatric cancers. Through widespread sampling of tumour, adjacent normal and distant normal samples at autopsy and whole genome sequencing, we aim to establish the point at which lethal paediatic brain tumours diverge from normal development. With many such tumours associated with germline predisposition mutations, we will also be able to investigate the tissue-specific effects these mutations induce.

  Study EGAS00001004771

• Prime editing for functional repair in patient-derived disease models

  Prime editing is a novel genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct a wide variety of genetic defects. We succeeded in efficient prime editing and functional recovery of disease-causing mutations in patient-derived liver and intestinal stem cell organoids. Whole genome sequencing of did not detect off-target mutations or a mutational signature induced by prime editing.

  Study EGAS00001004611

• Genetic subclone heterogeneity of tumor-initiating cells in human colorectal cancer

  A subset of tumor-initiating cells (TIC) drives colorectal cancer (CRC) progression in serial mouse xenografts. The TIC compartment itself is heterogeneous and comprises hierarchically organized long-term TIC, tumor transient amplifying cells, and delayed contributing TIC. To address the genomic heterogeneity of the CRC TIC compartment, genome-wide high-coverage whole genome sequencing was performed on patient tumors (n=3), corresponding serially passaged TIC-enriched spheres, and serial xenografts.HIPO P002

  Study EGAS00001001857

• Comparative genomics research for Chinese colorectal cancer

  In order to clarify the mechanisms of genesis and development of colorectal carcinoma, in this study, we performed comparative genomics research in Chinese colorectal cancer at various clinical stage via whole exon sequencing or whole genome sequencing. Comparative bioinformatical analysis was perform to find the difference on somatic single-nucleotide variants, short insert/deletion variants, genomic structural variants, and copy number variants between cancer tissue and normal tissue, or among cancer tissues at various clinical stages.

  Study EGAS00001002607

• International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia

  Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation (DNAme) patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML based on DNAme patterns are lacking. We therefore sought to define an international consensus for DNAme subgroups in JMML and develop classification methods for clinical implementation.

  Study EGAS00001004682

• UROMOL 2020 - SNP data

  The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters.

  Study EGAS00001004862

• Miseq (18S) analysis of spiked placental tissue samples

  We spiked a small number of placental tissue samples with different combinations of Candida albicans, Plasmodium falciparum, Toxoplasma gondii, Human Cytolomega virus and Salmonella bongori (various combination of the equivalents of 1, 10, 100, 1000 and 10000 genome copies). A DNA isolation was performed on these spiked samples and the resulting DNA was subsequently sequenced by MiSeq (18S). These same samples were also analysed by X Ten to allow for a sensitivity comparison of the two methods of the eukaryotic spiked signals (Candida albicans, Plasmodium falciparum and Toxoplasma gondii). In addition, non-spiked placental samples from 50 cases of Fetal Growth Restriction (FGR) (+ matched healthy controls) and 49 cases of Preeclampsia (+ matched healthy controls) and 100 preterm cases were analyzed for their non-human eukaryotic content.

  Dataset EGAD00001004197

• Sequencing of an organoid biobank for childhood soft tissue sarcoma.

  Rhabdomyosarcomas are diverse tumors of mesenchymal origin and the most common childhood soft tissue sarcoma. Patients receive intense treatment with a nevertheless poor prognosis for high-risk patients. New therapy would benefit from additional preclinical models and their rapid establishment. Tumor organoid models (tumoroids) have so far only been established from epithelial cancers. Here, we describe generation and characterization of a collection of pediatric RMS tumoroids comprising all major subtypes.

  Study EGAS00001005912

• The genomic landscape of recurrent ovarian high grade serous carcinoma: the BriTROC-1 study

  The BriTROC-1 study, spanning 15 centres across the United Kingdom, is a prospective observational project investigating putative causes of relapse in high-grade serous carcinoma (HGSC). Potential genomic changes associated with disease recurrence are examined by studying paired tumour samples collected from patients at diagnosis and after relapse after receiving platinum based chemotherapy. Shallow whole genome sequencing and targeted amplicon sequencing are used to identify copy number aberrations and short variants respectively.

  Study EGAS00001007292

• Stratton__WGS___RCC___Japan

  The Stratton team uses DNA sequencing for somatic mutations to advance understanding of the causes of cancer. In particular, the investigation of “mutational signatures”, which report the mutational processes operative over the lifetime of each individual, to understand whether they are generated by endogenous or exogenous exposures and the extent to which these vary between human populations. Our work brings together global cancer epidemiology and genomics and is particularly characterised by large-scale multinational studies.

  Study EGAS00001008001

• Nuclease deficiencies alter plasma cell-free DNA methylationprofiles (Human)

  The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.

  Study EGAS00001004897

• Genes___Health_imputed_genotype_dataset

  Genes & Health is a cohort of British Bangladeshi and British Pakistani individuals. In the Feb2020 data freeze, 28,022 individuals were genotyped on the Illumina Infinium Global Screening Array v3 chip (with the additional Multi-Disease variants). Imputation was performed using the Michigan Imputation Server with the GenomeAsia pilot reference panel, which contains 1,739 genomes and 642 from them are from South Asian groups. This dataset contains imputed SNPs with imputation accuracy >0.3 and MAF >0.1%.

  Study EGAS00001005373

• Investigation of the keratinocytic gene expression pattern in Hidradenitis suppurativa

  The underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression. To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.

  Study EGAS00001005544

• Mapping genetic effects on cell type-specific chromatin accessibility using single nucleus ATAC-seq

  Gene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 13 individuals. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type in a subset of 10 samples of European genetic ancestry.

  Study EGAS00001006184

• NEC

  This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR). Secondary outcomes were safety and objective response rate (ORR). Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. Feasibility of liquid biopsy by ctDNA was assessed.

  Study EGAS00001007013

• Epithelioid haemangioendothelioma (EHE) case series from the Stafford Fox Rare Cancer Program

  Nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program were collated via nation-wide referral to the Australian Rare Cancer Portal. Molecular analysis of RNA, DNA or both was possible in seven of nine cases. Survival was highly variable and unrelated to molecular profile. DNA sequences for two cases are deposited here.

  Study EGAS00001007474

• RNA sequencing in primary human macrophages overexpressing ETS2

  We investigated an intergenic haplotype on chr21q22, linked to five different inflammatory diseases, and discovered a mechanism that orchestrates macrophage responses during chronic inflammation. We delineated how the risk haplotype increases expression of the causal gene, ETS2, and demonstrated that ETS2 is necessary for inflammatory macrophage effector functions. To establish whether ETS2 is sufficient to drive inflammatory responses, we overexpressed ETS2 in a dose-dependent manner and performed RNA-sequencing to characterise the transcriptional effects.

  Study EGAS00001007554

• Anaplastic Oligodendroglioma AO Exome-seq data

  Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

  Dataset EGAD00001001452

• Genome Diversity in Africa Project - ancient samples - standard libraries

  Given the central importance of Africa to studies of human origins, genetic diversity and disease susceptibility, large-scale and representative characterisation of genetic diversity in Africa is needed. Analyses of ancient DNA from Africa would complement sequencing of modern African populations and provide unique opportunities to transform our understanding of the pre-history of the region. This approach would greatly refine our understanding of population structure and gene flow in Africa and globally, including genetic signatures of ancient admixture. This low coverage sequencing experiment will allow us to test and refine our pipeline for ancient DNA sequencing. 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/

  Dataset EGAD00001002211

• Variant calls for "Quality of Whole Genome Sequencing from Blood versus Saliva Derived DNA in Cardiac Patients"

  Paired blood and saliva samples from five unrelated individuals were directly compared for quality of whole genome sequencing. Two (Sample Pairs 1 and 2) were female probands diagnosed with tetralogy of Fallot, a type of congenital heart disease, and three (Sample Pairs 3, 4 and 5) were male probands diagnosed with hypertrophic cardiomyopathy. WGS was performed using Illumina HiSeq X to a target average coverage depth of 30x and a read length of 150 bp. The resulting reads were not filtered for minimum quality in order to avoid losing possible contaminant reads. Sequencing read alignment was done using Isaac Aligner to human genome build hg19. Short variant i.e. single-nucleotide variant (SNV) and small insertion-deletion (indel) calling was performed using Isaac Variant Caller with default parameters.

  Dataset EGAD00001005772

• Exome sequences of AL amyloidosis (ALA), multiple myeloma (MM) and ALA+MM hematological malignancies

  DNA was isolated from aberrant plasma cells (aPCs) and peripheral blood of 12 ALA, 10 ALA+MM and 29 MM individuals. DNA from aPCs was amplified using REPLI-g Mini Kit (Qiagen). Totally, we analyzed 51 patients, 102 samples. One batch of exome libraries (paired tumor-normal samples from 12 ALA, 10 ALA+MM and 6 MM) was prepared using SureSelect Human All Exon V5 Kit (Agilent Technologies) and sequenced on Illumina HiSeq 4000 platform, 100 cycles. Second batch (23 MM samples; IDs ARK01-ARK26) was prepared using SureSelect Human All Exon V5 + IGH, IGK, IGL, MYC (Agilent Technologies) library preparation kit and sequenced on Illumina HiSeq 2000 platform in paired-end settings, 75 cycles. The reads were mapped using BWA-MEM on human genome GRCh38 without alternate loci.

  Dataset EGAD00001006047

• Novel de novo pathogenic variant in the GNAI1 as a cause of severe disorders of intellectual development with autistic features

  Our probands A and B are boys-monozygotic twins with the clinical diagnosis of severe intellectual impairment, developmental stagnation, and dysphasia. They were diagnosed at the Department of Medical Genetics and Genomics (University Hospital Brno). Parents provided written informed consent, which was approved by the Research Ethics Committee of Masaryk University and Ethics Committee of University Hospital Brno. Peripheral blood samples were collected in sterile heparinized tubes for cytogenetic analysis. Genomic DNA samples were obtained from 1 ml peripheral blood in EDTA, according to the standard DNA isolation process using the MagNaPure system (Roche Diagnostics, Basel, Switzerland). Quality and quantity were checked using a DeNovix DS-11 Spectrophotometer (DeNovix Inc., Wilmington, DE, USA) and Qubit® 2.0 (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

  Dataset EGAD00001007736

• Disease specific alterations in the olfactory mucosa of patients with Alzheimer’s disease

  The sample AD_Library_1, AD_Library_2 and Control_Library were run on a Chromium Chip B with the Chromium Single Cell 3′ Library & Gel Bead Kit v3 kit (10x Genomics, CA, USA) . The 3’ gene expression libraries were sequenced at an approximate depth of 50,000 reads per cell using the NovaSeq 6000 S1 (Illumina, San Diego, CA, USA) flow cells. Cell Ranger v.3.0.2 was used to analyze the raw base call files. FASTQ files and raw gene-barcode matrices were generated and aligned human genome GRCh37 (hg19). The samples were integrated in R v.4.0.3 and generated Seurat objects, two related to AD samples and one to control samples, were analyzed using the Seurat package v.4.0.3 to perform downstream analysis, clustering of the cells and differential expression.

  Dataset EGAD00001008560

• Bulk-tissue RNA-sequencing paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control individuals ( anterior prefrontal cortex & cerebellar cortex – 4 individuals, putamen- 3 individuals)

  Profiling of paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen samples by bulk-tissue RNA-sequencing. Samples were derived from 4 post-mortem neuropathologically-confirmed control individuals ( anterior prefrontal cortex – 4 individuals, cerebellar cortex – 4 individuals, putamen- 3 individuals). Paired-end FASTQ files for each of the human samples are provided. Fastp (v 0.20.0), a fast all-in-one FASTQ pre-processor, was used for adapter trimming, read filtering and base correction. Fastp default settings were used for quality filtering and base correction. Further details on parameters used are available here: https://github.com/RHReynolds/RNAseqProcessing .

  Dataset EGAD00001009264

• WGS/WES analysis refines molecular subtypes of hepatocellular carcinoma

  This work aims to identify homogeneous and robust molecular subtypes in HCC based on a large, homogenous and well-annotated cohort. We performed whole genome/exome sequencing (WGS/WES) on 529 HCC from 461 patients collected mainly in France. Based on the genomic data, we identified 9 robust HCC subtypes primarily driven by key mutations. We further characterized these subtypes using genomic and clinicopathological features. Among the 9 subtypes, 5 belonged to chromosome instable tumors, while 3 belonged to chromosome stable tumors. Our subtypes were associated with prognosis and showed distinct distributions across features like etiology and gender. This study offers a comprehensive molecular classification of HCC, enhancing our understanding of hepatocarcinogenesis and supporting the development of genome-based precision medicine for liver cancer.

  Dataset EGAD00001015428

• Acral Melanoma PDXs from the admixed Brazilian Population- Tumour RNA expression data - htseq count files

  Files containing the read counts obtained with obtained with HTSeq for all the genes in Ensembl v103 annotation for GRCh38 human reference genome. This dataset contains the files for all Tumour samples. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

  Dataset EGAD00001015745

• A developmental cell atlas of the human thyroid gland

  Thyroid hormones are essential for health, but human thyroid development and cellular heterogeneity are poorly understood. We generated a high-resolution, spatiotemporal transcriptional atlas of human fetal thyroid, and examined its perturbations in trisomy 21 (T21), where aberrant thyroid development is associated with congenital hypothyroidism, and in papillary thyroid carcinoma (PTC). Normal tissue revealed two functional follicular cell states (fTFC1, fTFC2) with divergent PAX8 expression levels, persisting into adulthood. Additionally, the rare C-cell population was comprehensively profiled at single-cell resolution for the first time. T21 fetal thyroid was hypoplastic, with disrupted follicular morphology and altered expression of genes mediating cellular topology and extracellular matrix interactions. Finally, the transcriptional signals of both fetal follicular cell states were found to be perturbed in PTC. Overall, we defined a reference atlas for normal human fetal thyrocyte heterogeneity and provided novel insights into thyroid disorders.

  Dataset EGAD00001015783

• Genetic Variation and Signatures of Natural Selection in Diverse Africans

  Our study identified candidate regions of genome involved in adaptation and identified regions associated with selected phenotypes.

  Study phs000449

• COVID-19 progression and convalescence in common variable immunodeficiency patients

  Longitudinal analysis of single-cell RNAseq datasets of PBMCs from COVID-19 CVID patients and controls.

  Study EGAS50000000368

• Macrophage polarisation to M1 and M2 phenotypes

  iPSC-derived macrophages were polarised with LPS/IFN-gamma or IL4 to M1 and M2 phenotypes, respectively.

  Study EGAS50000000820

• NeoPAL study - RNAseq and Targeted DNA sequencing data

  This dataset is composed of 159 RNAseq data (fastq, bam and count tables) and 35 targeted DNAseq data (fastq).

  Dataset EGAD50000001490

• Ion Proton WES raw and processed data from and novel immunodeficiency proband.

  BAM and VCF files from WES of an affected proband with a novel immunodeficiency phenotype caused by homozygous mutation of SLC19A1.

  Dataset EGAD50000000524

• AI

  Allelic imbalance (AI) region calls: start and end positions and the measured mBAF and LRR mean of each region after the BAF segmentation algorithm. Software: Illumina GenomeStudio;PennCNV v. 1.0.4;BAF segmentation v1.2.0.

  Dataset EGAD00010001926

• DNA methylation array study for 7 pairs of primary NSCLCs and distant metastases

  This study is to compare DNA methylation profiles between primary NSCLCs and paired distant metastases.

  Study EGAS00001004079

• SNP genotyping of multiplex autoimmune Addison's families from the UK and Norway

  Multiplex AAD families from the UK and Norway, genotyped on the Affymetrix SNP 6 array

  Study EGAS00001001237

• WES cutaneous and uveal melanoma liver metastases

  Whole exome sequencing analyses of tumor liver metastases from untreated cutaneous melanoma (CM) and uveal melanoma (UM) patients.

  Study EGAS00001004795

• Whole exome and transcriptome sequencing of gastric cancer patients

  Whole exome and RNA-seq of matched normal gastric mucosa (n=34) and gastric cancer tissues (n=34) from gastric cancer patients (n=34)

  Dataset EGAD00001004164

• ChIP-seq in colorectal cancer and paired adjacent normal mucosa

  Chip-seq samples for 20 colorectal patients with paired adjacent normal mucosa to characterize H3K27ac and H3K4me1.

  Study EGAS00001005303

• G&T-seq: Parallel sequencing of single-cell genomes and transcriptomes

  Development of a method for separation and parallel sequencing of the genomes and transcriptomes of single cells.

  Dataset EGAD00001001332

• Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer

  Dataset consists of 216 samples, with each sample having a BAM, BAI and VCF file.

  Dataset EGAD00001011297

• The University of Hong Kong Intestinal Metaplasia Organoids Study scCNV Data

  Single cell encapsulation and DNA libraries were prepared by Chromium™ Single Cell DNA Reagent Kits and Chromium™ Single Cell C and D Chip Kits.

  Dataset EGAD00001015423

• Genetic architecture of male infertility in India

  The dataset consists of whole exome and genome sequencing data from infertile males and his parent(s) and/or sibling(s)

  Dataset EGAD00001015606

• NHLBI: Genetic modifiers of sickle cell anemia severity and fetal hemoglobin expression in the Cooperative Study of Sickle Cell Disease (CSSCD)

  Phenotypic heterogeneity is characteristic of sickle cell anemia, a Mendelian disorder caused by homozygosity for the sickle HBB gene (glu6val). Patients have different rates of hemolysis/vasculopathy and viscosity/vasoocclusion-related complications. These complications account for a substantial reduction in life expectancy. In 1994, the median life expectancy for men and women with sickle cell anemia was 42 and 48 years, respectively, and despite many advances in care, the annual mortality still approaches 4%. Fetal hemoglobin (HbF) is one of the most studied markers of severity of sickle cell anemia, and detailed longitudinal measurements were taken on subjects enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cubic root transformation of the median values from follow-up in 848 African American subjects is the phenotype data used in the GWAS of fetal hemoglobin. The analysis was adjusted by sex. Details are in Solovieff et al., Blood 2010 [PMID: 20018918]. To integrate individual disease complications into a comprehensive measure of severity, we developed a model of the associations among clinical and laboratory variables that scored disease severity as the risk of death within 5 years. This network was developed using data obtained from more than 3,400 subjects from the CSSCD, and its accuracy was validated in two unrelated sets of sickle cell patients. Recently, the network was also validated in a small European cohort of patients with sickle cell anemia. We used extreme values of disease severity as cases and control in the GWAS of severity of sickle cell anemia. We conducted the GWAS in 1,265 patients with either "severe" (177) or "mild" disease (1088) based on a network model of disease severity. Details are in Sebastiani et al. Am J Hematol, 2010 [PMID: 20029952].

  Study phs000366

• A Missense SNP in the Tumor Suppressor SETD2 Reduces H3K36me3 and Mitotic Spindle Integrity in Drosophila

  While examining DNA from renal cell carcinoma (RCC) patients we observed a single nucleotide polymorphism (SNP; rs58906143,chr3:47163422 C→G (hg19); E902Q*) within SETD2 that was overrepresented in kidney cancer patients compared to control patients. This original study utilized directed sequencing of 14 genes. In an expanded study using a Taqman assay to study the specific SNP, a G allele was found in 72/493 cases (14.6%) and 24/356 (6.7%) controls. Analysis by ancestry revealed that there was there was a G allele in 50/119 (42.0%) cases and 21/71 (29.6%) controls in patients with African Ancestry while there was a G allele in 19/335 cases (5.7%) and 3/269 (1.1%) controls in patients with European Ancestry. These differences did not reach statistical significance. Concurrently, we studied the functional effect of this SNP in a Drosophila model. The homologous amino acid substitution at E741Q reduces H3K36me3 levels which could be rescued by wild type Set2. Additionally, the mutation resulted in significant defects in spindle morphogenesis, consistent with a role for SETD2 in alpha-tubulin methylation during mitosis. Data available through dbGAP include the 14 gene sequence files of 52 control and 128 RCC patients, the results of Taqman SNP (rs58906143) analysis in text files for 221 controls and 357 RCC patients, and compiled phenotype data including age and assigned race. Due to data use limitations, genotyping data for 8 RCC patients and 83 controls as well as GWAS data for ancestry determination will not be available on dbGaP, but will be made available on request.

  Study phs003474

• Response and Resistance to ER-Directed Therapy in Metastatic Breast Cancer

  Despite the reduction in cancer recurrence and mortality provided by hormonal therapy, estrogen receptor positive (ER+) metastatic breast cancer (MBC) remains the most common cause of breast cancer death, resulting in more than 20,000 deaths in the U.S each year. Although several therapeutic options exist to target the estrogen receptor, resistance to these therapies invariably occurs. Genetic mechanisms of acquired resistance to targeted therapies in ER+ MBC are not well understood. To address this, we developed a prospective biopsy protocol where multiple research biopsies are collected from metastatic samples and used for pathology, ER/PR/HER2, OncoPanel (a CLIA 300 gene sequencing panel), whole exome sequencing (WES), transcriptome sequencing (RNA-Seq), and single-cell RNA-seq (scRNA-seq). In some cases, tissue is used for cell line and xenograft generation. Archival primary biopsies are also obtained when possible for parallel genomic studies. Patients are followed and serial metastatic biopsies are obtained. This data will be used to determine the landscape of genomic alterations in treatment-resistant ER+ MBC, and compared to data generated by TCGA for treatment-naive ER+ primary breast cancer. Comparison of genomic studies from resistant, metastatic specimens with corresponding pre-treatment primary samples will allow us to identify genomic association with resistance to specific therapies. Analysis of the serial metastatic biopsies collected over the course of multiple treatments will also shed light on tumor evolution under selective therapeutic pressure.NoteA subset of the MBC blood biopsies that are included in our study can be accessed and downloaded from the phs001977 accession.Another subset of patients in this study participated in a clinical trial (NCT02871791) and have their data deposited in the current study as well.

  Study phs001285

• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia

  Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. Consequently, CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.

  Study EGAS50000000933

• Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies

  Purpose: To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamics, and biomarker data of linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. Patients and Methods: In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Results: Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response. Conclusions: Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.

  Study EGAS50000000710