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• Whole-exome sequencing and microRNA profiling predicted relapse risk of stage I lung adenocarcinomas

  Despite the advance in precision therapy, about 20% of stage I non-small cell lung cancer patients suffer a relapse after surgical resection. To develop molecular signatures for relapse prediction of stage I lung adenocarcinoma (LUAD), we conduct comprehensive analyses of multiplatform molecular profiling from 113 treatment-naïve stage I Taiwanese LUAD patients. We identify 16 nonsynonymous non-sporadic point mutations (NSPOPMs) harbored at EGFR, KRAS, TP53, CTNNB1 and 6 other genes, and find that the Non-EGFR NSPOPMs were associated with early relapse in a dose-dependent manner via variant allele fraction (VAF). We define a score, maxVAF, to aggregate the VAFs of these NSPOPMs by the maximum value. MicroRNA expression analysis shows a strong correlation between miR-31 and maxVAF. Combining maxVAF with miR-31 led to a powerful risk prediction for surgically resected stage I patients (hazard ratio = 8.65, P = 0.001). Our study opens up more options for precision management of stage I LUAD patients.

  Study EGAS00001004461

• Proteogenomic Analysis of CALGB40601 (ALLIANCE) a Neoadjuvant Phase III HER2-Positive Breast Cancer Trial

  80 frozen core needle biopsies from 54 HER2+ breast cancer patients from the CALGB 40601 trial (NCT00770809) were processed for proteogenomic analysis to identify genes, proteins, and phosphosites associated with pathological complete response to neodjuvant anti-HER2 therapies. The final set included 22 patients treated with trastuzumab plus lapatinib in combination with pacletaxel (THL arm), 24 patients treated with trastuzumab in combination with pacletaxel (TH arm), and 8 patients treated lapatinib in combination with pacletaxel (TL arm). Principal findings of this study included identifying negative cases misdiagnosed as HER2+ that did not respond to targeted therapy and observing higher levels of two biomarker candidates in non-pCR tumors. Mass spec-based proteomics and phosphoproteomics data generated from 75 biopsies (all 54 patients) will be made available via the Proteomic Data Commons. Whole exome- (67 biopsies from 49 patients) and RNA-sequencing (52 biopsies from 39 patients) data for the subset profiled with proteogenomics will be made available through dbGaP, but genomic and transcriptomic profiling data for the whole cohort has previously been deposited (phs001570).

  Study phs003576

• The data access committee for Genome-wide analyses of cell-free DNA for therapeutic monitoring of patients with pancreatic cancer

  Dac EGAC50000000588

• Osteosarcoma Genomics

  In this study we attempt to elucidate the genomic characteristics of osteosarcoma. Clinical characteristics 58 tumor / normal pairs from 58 patients were included in the study. Median age at diagnosis was 12 years. 49% of the patients were male and 47% had metastases at diagnosis. 5 year overall survival was 49% for the entire population, 33% for patients with metastatic disease and 64% for patients with localized disease. Patients with metastatic disease at diagnosis had a significantly worse overall survival. All cases except 2 were sporadic and no patients had stigmata of Rothmund-Thomson, Bloom's or Werner's syndromes or Paget's disease. Two familial cases were affected siblings from a family in which there were 2 unaffected parents and 2 unaffected siblings. None of the patients had known Li Fraumeni or hereditary retinoblastoma. Sample Selection and Clinical Data Samples were contributed by hospitals in Brazil, Spain, Mexico and the United States. All patients had histopathology confirmed to be osteosarcoma by a pathologist at the local institution. All but 5 tumor specimens sequenced were obtained pre-chemotherapy from the primary tumor at the time of diagnosis. 2 tumor specimens were obtained pre-chemotherapy from a metastatic tumor at the time of diagnosis. 3 tumor specimens were obtained post-chemotherapy from a metastatic tumor.

  Study phs000699

• Whole genome sequencing to detect spontaneous acquired mutations in mismatch repair-deficient human colon organoids

  Individual outgrowing organoids surviving the medium-based selection were manually picked and propagated as clonal lines for a couple of passages to avoid unexpected mutation accumulation before being harvested for WGS/WES. 1 µg of DNA was used for WGS/WES by Agilent SureSelect V7 kit, with 8Gb per sample (50X average mapped) data throughput, sequencing on NovaSeq 150PE

  Study EGAS50000000114

• Next Generation Sequencing to Predict Risk of Events from Coronary Artery Disease

  Coronary artery disease (CAD) and myocardial infarction (MI) remain the leading cause of death worldwide and in the US. In recent years, clinical studies that considered intermediate phenotypes (phenotypic or genomic data isolated between DNA and the main disease phenotype) have greatly enhanced our understanding of complex traits like CAD by enabling inference of biological networks from the combination of genetic and genomic datasets isolated from disease-relevant tissue(s). The NGS-PREDICT study used whole transcriptome sequence data generated from primary macrophages derived in vitro from venous blood that was obtained from CAD cases and non-CAD controls. This study provided a valuable resource for the validation of biomarkers identified in STARNET NGS data from macrophages obtained from patients with and without CAD. It also can be used as a reference dataset for the study of metabolic syndrome as well as other systemic inflammatory diseases.

  Study phs003883

• Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To determine the sensitivities and specificities of ventillation/perfusion (V/Q) lung scans for acute pulmonary embolism (PE).Participants: A total of 1487 participants were enrolled.Conclusions: Almost all participants with pulmonary embolism had abnormal scans of high, intermediate, or low probability, but so did most without pulmonary embolism. Only in a minority of participants did the clinical assessment combined with the V/Q scan interpretation improve the overall chance of reaching a correct diagnosis of acute PE. Although a high probability scan usually indicated the presence of PE, only a small number of participants with PE had a high probability scan. Reference: PIOPED Investigators, 1990, PMID: 2332918.

  Study phs004020

• Dynamics of sequence and structural cell-free DNA landscapes in small-cell lung cancer

  Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time non-invasive biomarkers of therapeutic response. We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received systemic treatment with chemotherapy or immunotherapy-containing regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy. Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for assessment of ctDNA molecular response in all patients. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared to radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank p=0.0006) and progression-free (log-rank p<0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. ctDNA analyses provide a rapid approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring.

  Study EGAS00001006831

• Distinct evolutionary trajectories of primary high grade serous ovarian cancers revealed through spatial mutational profiling

  High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to emergence of treatment-resistant sub-clones. We sought to measure the degree of genomic diversity within primary, untreated HGSC to examine the natural state of tumor evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on thirty-one spatially and temporally separated HGSC tumor specimens (six patients) including ovarian masses, distant metastases, and fallopian tube lesions. We found widespread intra-tumoral variation in mutation, copy number, and gene expression profiles, with key driver alterations in genes present in only a subset of samples (e.g. PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range: 10.2% to 91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology with common etiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating diversity arises at early stages of tumorigenesis. Our results reveal that HGSC exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug resistance mechanisms.

  Study EGAS00001000547

• Exome sequencing from cfDNA blood samples. 159 samples at 2x101bp Illumina reads in Fastq format.

  Differential presence of exons (DPE) by next generation sequencing (NGS) is a method of interpretation of whole exome sequencing. This method has been proposed to design a predictive and diagnostic algorithm with clinical value in plasma from patients bearing colorectal cancer (CRC). The aim of the present study was to determine a common exonic signature to discriminate between different clinical pictures, such as non-metastatic, metastatic and non-disease (healthy), using a sustainable and novel technology in liquid biopsy. Through DPE analysis, we determined the differences in DNA exon levels circulating in plasma between patients bearing CRC vs. healthy, patients bearing CRC metastasis vs. non-metastatic and patients bearing CRC metastasis vs. healthy comparisons. We identified a set of 510 exons (469 up and 41 down) whose differential presence in plasma allowed us to group and classify between the three cohorts. Random forest classification (machine learning) was performed and an estimated out-of-bag (OOB) error rate of 35.9% was obtained and the predictive model had an accuracy of 75% with a confidence interval (CI) of 56.6-88.5. In conclusion, the DPE analysis allowed us to discriminate between different patho-physiological status such as metastatic, non-metastatic and healthy donors. In addition, this analysis allowed us to obtain very significant values with respect to previous published results, since we increased the number of samples in our study. These results suggest that circulating DNA in patient’s plasma may be actively released by cells and may be involved in intercellular communication and, therefore, may play a pivotal role in malignant transformation (genometastasis).

  Study EGAS00001006656

• Psoriasis Patient PBMC scRNA-seq data

  This dataset contains raw and processed data of four scRNA-seq PBMC samples from four Psoriasis patients (Pso3 = male, Pso4 = female, Pso7 = female, Pso8 = male). Raw sample libraries were prepared with 10x 5'-kit v2 multiplexing the individual samples using TrueSeq barcoded antibodies to stain the cells. Resulting sequencing data consists of four FASTQs (2 x antibody multiplex to demultiplex the samples + 2 x transcriptome data containing the typical cell x UMI barcode data for count matrix generation). The raw sequencing data was processed with cellranger 6.0.1 with the GRCh38 3.0.0 reference and cell to sample assignment was subsequently done with couhto 1.1.0 (https://github.com/dmalzl/counhto) employing the same algorithm as cellranger multi (couldn't be used here though as multi does not handle 5'-chemistry data). Processed data contains all main outputs of cellranger count in raw text format or in h5 formats including the used feature reference for (i.e. antibody barcode to sample assignment) as well as the computed cell to sample assignment computed by counhto. For further details including all used code in the analysis of the data please consult https://doi.org/10.5281/zenodo.13846873

  Dataset EGAD50000001102

• An Omics View of Asthma through Monozygotic Twins

  The etiology of asthma involves both genetic and non-genetic factors. We performed whole transcriptome sequencing on monozygotic twins discordant or concordant for asthma (with concordant healthy twins as controls), and identified multiple potential transcriptomic profiles associated with the asthma phenotype.

  Study phs000886

• Comprehensive molecular and clinicopathological profiling of desmoid tumors

  Previous studies have not clearly identified a prognostic factor for desmoid tumors (DT). Whole-exome sequencing and/or RNA sequencing were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics.

  Study JGAS000270

• Evaluation_of_size_selection_on_cancer_specific_sequencing_libraries

  A couple of previously characterized and sequenced libraries will be repeated using a couple of differing size selection criteria and skim sequenced using an Illumina HiSeq. The resulting sequence will be analyzed to determine the optimal DNA library size for our specific downstream analysis.

  Study EGAS00001000293

• WNT7B-reporter organoids sorted

  Transcriptomic data from pancreatic ductal adenocarcinoma (PDAC) organoids to investigate the role of WNT7B. This dataset includes: - Bulk mRNA sequencing of WNT7B-reporter pancreatic ductal adenocarcinoma (PDAC) organoids sorted for cells displaying low, medium and high expression of the reporter

  Study EGAS50000001543

• 10x Genomics BCR Sequencing

  BCR sequencing done with 10x Genomics V(D)J kit + platform for the paper: Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma. Dataset contains paired FASTQ files for 35 samples, each was processed with the 10x Genomics V(D)J kit to obtain the sequence of the B-cell receptor sequence.

  Dataset EGAD50000001373

• SCIMAP PILOT D21

  This dataset includes the RNA-seq and ATAC-seq fastq files, as well as the Cellranger ARC count table, for the first experiment with multimodal sequencing in the SCI-MAP project (1 sample). Here, human induced pluripotent stem cells underwent differentiation to chondrocytes for 21 days following an established protocol. Nuclei were isolated and sequenced in two modalities simultaneously; RNA and ATAC.

  Dataset EGAD50000001516

• Low-input RNA-seq libraries from FFPE samples using TaKaRa SMARTer kit

  Using the TaKaRa SMARTer Stranded Total RNA-Seq Kit v2, RNA-seq libraries were generated from 5 ng of RNA extracted from FFPE tissue. A low-input workflow was applied with 5 PCR cycles for the first amplification and 16 for the second. Library quality was assessed by Bioanalyzer and Qubit, and libraries were sequenced (2×150 bp) on the Illumina NextSeq 550 platform.

  Dataset EGAD50000001552

• Hybrid untargeted and targeted RNA sequencing facilitates genotype-phenotype associations at single-cell resolution

  Raw sequencing data for the manuscript "Hybrid untargeted and targeted RNA sequencing facilitates genotype-phenotype associations at single-cell resolution". It includes PacBio long-read scRNA-seq, illumina short-read scRNA-seq and Twist-based targeted scRNA-seq datasets for two adrenal samples.

  Study EGAS50000001537

• RNAseq of 12q-amplified osteosarcomas

  RNA-seq of 12q-amplified osteosarcomas for detection of gene fusions and gene expression analysis. RNA-seq was used to look for novel gene fusions and promoter swapping events, and study the expression levels of identified 3' partners. Additionally, global gene expression patterns were used to separate cases into clusters.

  Study EGAS50000000494

• February 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  February 2020 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001006220

• January 2018 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

  January 2018 data update (bam/fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

  Dataset EGAD00001003962

• Genome Wide Association Studies in ECOG 2997 Trial

  The ECOG 2997 trial was a randomized controlled trial for patients with previously untreated CLL comparing fludarabine monotherapy to the combination of fludarabine and cyclophosphamide. The initial clinical findings of this study were published in the Journal of Clinical Oncology in 2007 (JCO 25:793-8). Additional laboratory studies have also published (JCO 25:799-804).

  Study phs000621

• Signals of positive selection in Peruvians from three ecological regions

  In this study, genome-wide single-nucleotide polymorphism (SNP) data (Illumina Infinium® MEGA array) was gathered for 200 individuals distributed across Perú, and then analyzed to investigate signals of recent positive selection specific to populations living in the high-altitude environments of the Andes, the arid Pacific coast and the Amazon rainforest.

  Study EGAS00001005692

• Clonal architectures predict clinical outcome in clear cell renal cell carcinoma

  We analyze the clonal architectures of ccRCC patients from three different populations, including TCGA, Japanese and Chinese patients. We characterize the mutational signatures across different populations and evolution stages. The TCGA and Japanese data sets were downloaded from published studies and we also generated the whole genome sequencing data for more than 40 Chinese patients.

  Study EGAS00001003447

• Molecular Profiling and Sequential Somatic Mutation Shift in Hypermutator Tumors Harboring POLE Mutations

  Defective DNA polymerase ? (POLE) proofreading leads to extensive somatic mutations that exhibits biased mutational properties; however, the characteristics of POLE-mutated tumors remain unclear. In present study, we described a molecular profile using whole exome sequencing based on the transition of somatic mutations in 10 POLE-mutated solid tumors that obtained from 2,42 Japanese patients. The bias of accumulated variations in this mutant was quantified to follow a pattern of somatic mutations, thereby classifying the sequential mutation shift into three periods. During the period prior to occurrence of the aberrant POLE, no accumulation of mutations in cancer-related genes was observed, whereas PTEN was highly mutated in conjunction with or subsequent to the event, suggesting that POLE and PTEN mutations were responsible for the development of POLE-mutated tumors. Furthermore, homologous recombination was restored after occurring PTEN mutations. Our strategy for estimation of the footprint of somatic mutations may provide new insight toward the understanding of mutation-driven tumorigenesis.

  Study JGAS000130

• WTCCC2 Bacteraemia Susceptibility (BS) samples

  A WTCCC2 project genome-wide association study for bacteraemia susceptibility in 4924 individuals from Kenya, genotyped on the Affymetrix 6.0 array.

  Study EGAS00001001756

• miRNA

  miRNA Sequencing of olfactory mucosa (OM) cells derived from cognitively healthy and individuals with AD exposed to traffic-related ultrafine particles (UFPs) for 72h in submerged cultures. The UFPs used for exposures were: A0 and A20. Exposures were compared to the corresponding blank samples.

  Dataset EGAD50000001532

• Dataset for transcriptome sequencing of chordoma cells

  This dataset contains transcriptome sequencing for 15 samples from chordoma cells. The sequencing was performed on Illumina HiSeq 4000 and Illumina NovaSeq 6000. The sequencing was always paired.

  Dataset EGAD00001015642

• Reference exome data for a Northern Brazilian population

  Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

  Dataset EGAD00001006407

• ChIP-Seq data for the paper titled "Orthotopic Patient-Derived Xenografts of Pediatric Solid Tumors"

  ChIP-Seq data for the paper titled "Orthotopic Patient-Derived Xenografts of Pediatric Solid Tumors"

  Dataset EGAD00001003432

• Dac for "MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection"

  Dac for the Study "MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection" registered for Frank Momburg, f.momburg@dkfz-heidelberg.de Marten Meyer, marten.meyer@dkfz-heidelberg.de

  Dac EGAC50000000064

• RNA sequencing of baseline HCC PDX models

  To establish the baseline transcriptional profiles, we performed bulk RNA-seq for 36 of our HCC PDX models. 2-6 samples were collected for each model resulting in a total of 68 samples. Isolated RNA was used as input for library preparation using TruSeq RNA Sample Preparation Kit v2 (Illumina). The libraries were multiplexed and sequenced on Illumina HiSeq 2500 (Illumina) to produce FASTQ files.

  Dataset EGAD50000000736

• The data access committee for Single molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer

  Dac EGAC00001003253

• Fastq files for SAIF genome

  This dataset contain the raw files generated for SAIF genome project

  Dataset EGAD00001000254

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

  COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

  Study EGAS00001005634

• Exome & MiSeq sequencing of individuals with Huntington's disease

  The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

  Study EGAS00001006383

• CoV2 challenge data

  Repository containing the transcriptomic data for the CoV2 challenge study

  Dac EGAC50000000391

• H3N2 challenge data

  Repository containing the transcriptomic data for the H3N3 challenge study

  Dac EGAC50000000379

• Adipocytes Regulate Fibroblast Function and Their Loss Contributes to Fibroblast Dysfunction in Inflammatory Diseases

  We profiled live synovial cells from 16 individuals with no diagnosed arthritis using single-cell RNA sequencing. Our study was designed to provide a reference single cell RNA sequencing dataset for researchers interested in studying arthritic synovium, providing sequencing data on healthy synovial cells for comparison to cells from diseased synovial tissues. Synovial tissue was collected post-mortem from three different sources between 2019-2021: the National Disease Research Interchange, a collaboration with Rush University and the Gift of Hope, and the Brigham and Women's Hospital Autopsy Department. To be included in the study, patients had to be between the ages of 18 to 72 and have no diagnosed arthritis or autoimmune diseases. Additionally, this study includes bulk RNA sequencing data of cultured primary synovial fibroblasts isolated from three rheumatoid arthritis patents. Cells were stimulated with either cortisol, fat conditioned media, TGFβ, TNFα, fat conditioned media with mifepristone, TGFβ with fat conditioned media, or TNFα with fat conditioned media. Cells were harvested 4 or 22 hours later and lysates collected for sequencing. Data from this study submitted to the Gene Expression Omnibus (GEO) may be accessed via accession number GSE233504.

  Study phs003304

• ARAF Mutations Confer Resistance to RAF Dimer Inhibitor Belvarafenib in NRAS- and BRAF- Mutant Melanoma

  Belvarafenib, a potent and selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant melanoma patients. Here, we report the first-in-human phase I study investigating maximum tolerated dose, assessing safety and preliminary efficacy of belvarafenib in BRAF- and RAS-mutated advanced solid tumors (NCT02405065, NCT03118817). Through generation of belvarafenib resistant NRAS- mutant melanoma cells and analysis of circulating tumor DNA from patients treated with belvarafenib, we identified novel recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and kinase activity- dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Taken together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

  Study EGAS00001005086

• Joslin Study on the Genetics of Type 2 Diabetes

  Between 1993 and 2003, families were recruited in the Joslin Study on the Genetics of Type 2 Diabetes for the presence of an autosomal dominant mode of inheritance of diabetes. Recruiting and screening of families occurred through probands who were receiving medical care at the Joslin Clinic (Boston, MA). Screening of families included 1) a proband and at least one sibling with type 2 diabetes, 2) diabetes occurring in at least three generations, 3) diabetes inherited on one side of the prospective family. Probands had to have a diabetes diagnosis between the age range from 10 to 60 years. Demographic data, clinical data, and family history were collected from participating family members, along with blood and urine samples. This study includes genetic and phenotypic data from one family examined in Simeone, Wilkerson, et. al. (NPJ Genomic Medicine 2022, PMID: 35869090). Genotype data for 14 family members and whole genome sequencing data for 6 individuals were generated with the goal of identifying a potential genetic cause of disease in this family. To de-identify this family and protect confidentiality, information on sex in phenotype data and variants identified in X, Y, and MT chromosomes have been removed in compliance with IRB guidelines.

  Study phs002959

• FACS sorting of ploidy populations in an undifferentiated soft tissue sarcoma for RRBS

  Groups of cells belonging to different ploidy populations (based on PI staining) were collected from an undifferentiated soft tissue sarcoma. The different ploidy populations underwent RRBS, after which copy number signatures for the ploidy-sorted populations and the bulk population were extracted.

  Dataset EGAD00001008667

• T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases

  Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumour infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T cell infiltration in CLM using T cell receptor (TCR) repertoire sequencing. Eighty-five resected CLM from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T cell fractions were calculated, repertoire clonality was analysed based on Hill evenness curves, and TCR sequential convergence was assessed using network analysis. Increased T cell fractions (10.6% vs 6.3%) were detected in CLM exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT exposed tumours independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence. TCR repertoire sequencing can be used to quantify T cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T cell clonal expansion in CLM in a clinical context.

  Study EGAS00001007136

• Performance comparison of three DNA extraction kits on human whole-exome data from formalin-fixed paraffin-embedded normal and tumor samples

  We generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, Maxwell\textsuperscript{TM} RSC DNA FFPE Kit from Promega). Variant calling analysis shows a very high rate of concordance between matched FF / FFPE pairs and equivalent performance for the three kits we analyzed. We find a significant variation in the difference of total number of variants called between FF and FFPE samples for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results.

  Study EGAS00001002631

• cfMeDIP data for 72 VPC samples for validation

  We analyzed the cell free DNA methylomes using 72 plasma samples from patients with mCRPC prostate cancer in the VPC project for validation. Methylation was profiled using the methylated DNA immunoprecipitation coupled to next generation sequencing (MeDIP) technology. Files from multiple lanes exists per sample.

  Dataset EGAD00001008737

• MATISSE bulk RNA-sequencing data

  Tumor availability: Bulk RNA sequencing was performed on tumor biopsies of 48 patients at baseline and 45 patients across time points (baseline n=48, week 1 n=38, week 2 n=34, week 4 n=37), including lymph node metastasis that were sequenced in addition to the primary tumor. Tumor RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary tumor and lymph node metastasis sections containing at least 10% viable tumor cells present in the sample, except for on-treatment samples with a complete pathological response in which we isolated samples with at least 10% immune-infiltration with no viable tumor cells. A pathologist (LS) scored the tumor percentage and indicated the most tumor-dense region on a hematoxylin and eosin (H&E) stain slide for subsequent RNA isolation. According to the manufacturer's protocol, five to 10 FFPE slides (10 µm) were used for RNA isolation using the AllPrep DNA/RNA FFPE isolation kit (Qiagen, 80234) and the QIAcube. Genetic Diagnostics and Sequencing Services (CeGaT) performed RNA sequencing in Germany. Data processing: Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v2.20). Adapters of the reads (Pico v2 SMART adapter, first three nucleotides of the second sequencing read) were trimmed with Skewer (v0.2.2), without quality trimming. RNA-sequencing data was aligned to GRCh38 (Ensembl v109) using STAR (v2.7.9) in 2-pass mode with default settings. Gene counts were generated with the HTSeq (v2.0.2). FastQC (v0.12.1) and MultiQC (v1.14) were used for assessing data quality, on FASTQ files and intermediate processing steps.

  Dataset EGAD50000001470

• The analysis of mtDNA variability of the modern Polish population

  The aim of the present study was to define the mtDNA variability of Polish population. For the first time, the study of Polish population was conducted on such a large number of individuals (n=5800) representing administrative units of both levels of local administration in Poland (voivodeships and counties). Furthermore, the clusters were used as an additional form of population subdivision, corresponding to geographic regions of Poland.

  Study EGAS00001003309

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program – Sarcomas and other Solid Tumors

  The primary goal of this project involves the comprehensive molecular profiling of patient-derived xenograft (PDX) mouse tumor models. Molecular profiling of each PDX model will include whole exome sequencing (WES), RNAseq, MethylEPIC arrays, CytoSNP array, and DNA fingerprint for quality control. Limited clinical demographic data (e.g. diagnosis, disease site, disease status) will be obtained. This data can be utilized to validate PDX models with matched patient tumors and can be used to guide model selection for downstream preclinical drug testing.

  Study phs003161

• Transcriptome HCCO Hypoxia and Doxorubicin resistance

  We hypothesized that HCCO-intrinsic determinants of response to hypoxia or doxorubicin could be reflected in the gene expression profiles of the HCCOs. Therefore, we selected for comparative transcriptomic analysis two sets of 4 HCCO lines that were severely (hypoxia-sensitive) or barely affected (hypoxia-resistant) by hypoxia in an ATP-based proliferation assay or two sets of 4 HCCO lines whose doxorubicin response curves were clearly separated both under normoxic and hypoxic culture conditions for comparative transcriptomic analysis.

  Study EGAS50000000042