16459 results for "sec+and+unspecified+malignant+neoplasm"

in 59.51 milliseconds.

• Small molecule inhibitors of LOXL synergize with 5-AZA to restore erythropoiesis in myeloid neoplasms

  Objectives: Bone marrow (BM) stroma and microenvironmental factors in the BM milieu of myeloid neoplasms are increasingly being recognized as novel perspective therapeutic targets. Lysyl oxidases (LOX/LOXL) are crucial enzymes that cross-link collagen and contribute to the deposition of aberrant stiff extracellular matrix (ECM) in the BM of patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Here, we studied whether inhibition of LOX/LOXL enzymes produced by BM-derived MSCs favors the differentiation of MDS/MPN hematopoietic stem cell and progenitor cells (HPSCs) and enhances the effects of 5-azacytidine (5-AZA). Methods: Primary co-cultures of MSCs and HPSCs were established from n=31 MDS/MPN patients and treated with the pan-LOX/LOXL inhibitor PXS-5505, 5-AZA or the combination of both for 4 days. At the end of co-culture, HSPC differentiation was assessed by CFU assays and flow cytometry. In some of the experiments, MSCs monolayers were pre-treated or not with PXS-5505 for 6 days and decellularized using 20 mM ammonia. Subsequently, autologous HSPCs were cultured on ECM matrices in the presence of 5-AZA or PXS-5505 + 5-AZA combination with or without inhibitors of integrin signaling such as blebbistatin, Y-27632 and αvβ3-integrin blocking antibodies. Patient-derived xenografts (PDX) were established in NSG mice based on intrafemoral co-injection of HSPCs and autologous MSCs. PDX were treated with 3 cycles of 5-AZA (75 mg/m2), PXS-5505 (30 mg/kg on alternate days for the duration of 5-AZA treatment) or combination of both. Results: MSCs of MDS and MPN patients displayed significant overexpression of LOX/LOXL transcripts as compared to healthy age-matched controls. Remarkably, LOX/LOXL inhibition in MSCs/HSPCs co-cultures increased erythroid differentiation of patient HSPCs that had suboptimal or no response to 5-AZA alone. From a total of n=31 advanced stage MDS/MPN patients, n=11 (35.5%) responded to the combination treatment, which was evidenced by a significant increase of CD235a+CD45- erythroid cell production compared to 5-AZA/PXS/untreated arms (p<0.05). Of note, combination treatment with 5-AZA + PXS-5505 facilitated differentiation of CD235+ erythroid progenitors from HSPCs sub-clones with low mutational VAFs. The presence of MSCs was necessary for the effects of the combination treatment and required direct cell contacts between MSCs and HSPCs. Moreover, PXS-5505-mediated alterations of the ECM composition alone were sufficient to induce erythroid differentiation. Inhibition of integrin-mediated signaling using blebbistatin, Y-27632 and αvβ3-integrin antibodies completely abrogated the effects of PXS-5505 induced erythroid differentiation. In vivo, the combination of PXS-5505 + 5-AZA favored erythroid differentiation of HSPCs and confirmed the in-vitro results. The combination treatment of 5-AZA + PXS-5505 induced the greatest reduction of disease burden as assessed by decrease of spleen indexes, total engraftment rates, BM fibrosis and mutational VAF profiles. Conclusions: The combination of 5-AZA + LOX/LOXL inhibitor PXS-5505 in MDS and MPN synergistically restores erythropoietic differentiation of primary HSPCs. The effect is dependent of contact interaction between HSPCs and niche components, such as MSCs and MSCs-derived ECM. Our data propose a strong rationale for a BM niche targeted combination treatment with 5-AZA + PXS-5505 in transfusion dependent MDS and MPN, which will be assessed in forthcoming clinical trials.

  Study EGAS00001006174

• WES of precancerous lesions from 10 lynch patients and 3 sporadics

  Raw sequencing data of WES that were obtained from precancerous samples as adenoma and MMR-deficient crypts and paired healthy tissue from MSI CRC patients of which 10 are diagnosed with lynch syndrome and 3 had sporadic cancer. These data were analyzed in order to evaluate microsatellite instability though tumorigenesis and associated to splicing deregulation in MSI tumors RNA.

  Dataset EGAD50000000644

• WES of breast cancer patients and controls

  Investigation of post-zygotic and germline variants using whole exome and ultra-deep duplex sequencing in paired uninvolved margin and primary tumor samples from 126 breast cancer patients with differing survival outcomes, with skin or blood samples as reference. Pairs of uninvolved margin and blood samples were also collected for 15 reduction mammoplasty patients without personal or familial history of cancer, serving as controls.

  Dataset EGAD50000000770

• Single-cell somatic copy number variants in brain using different amplification methods and reference genomes

  Low coverage paired end Illumina WGS from cells amplified with Picoplex, PTA, and droplet MDA. Two brains with Multiple System, Atrophy, one control, and non-brain controls (fibroblasts, NA12878)

  Study EGAS50000000020

• Development of a rapid and comprehensive genomic profiling test supporting diagnosis and research for gliomas

  Targeted sequencing dataset used for the paper entitled "Development of a rapid and comprehensive genomic profiling test supporting diagnosis and research for gliomas". The cohort includes 53 cases of targeted DNA squencing, 15 of them have matched control sequences. The capture panel was made by Agilent SureSelect and the sequence was performed using DNBSEQ or Illumina sequencer.

  Dataset EGAD50000000979

• Bulk-RNAseq from human nerve fascicles and Schwann cells

  Bulk-RNAsequencing from human nerve fascicles from patients with polyneuropathies, and human Schwann cell cultures isolated from said nerve fascicles, in comparison to control human Schwann cell cultures and a referential fibroblast culture.

  Study EGAS50000000737

• The study on genomic profiling using clinical specimens (tissue, blood, etc.) form patients with lung and thymic tumors

  The objective is to generate a comprehensive immunogenomic profiling in thymoma using RNA sequencing and TCR repertoire analysis and to evaluate the potential of immunotherapy in thymoma from multiple perspectives.

  Study JGAS000552

• Genomic and transcriptomic analysis on hepatocarcinogenesis after HCV eradication

  Little is known about the genomic and transcriptomic features of hepatocellular carcinoma developing after HCV eradication (SVR-HCC). In this study, we aimed to unveil the genomic and transcriptomic basis of hepatocarcinogenesis after SVR.

  Study JGAS000234

• Single Cell RNAseq of blood and tumor from renal cancer patients

  Single-cell RNASeq (scRNAseq) showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and high IL8 expression was associated with the downregulation of the antigen presentation machinery in myeloid cells.

  Study EGAS00001004230

• Whole genome sequencing and whole exome sequencing of mucosal melanoma

  We conducted whole genome sequencing of 5 mucosal melanomas and their matched DNA from blood. We conducted whole exome sequencing of a further 5 mucosal melanomas and their matched DNA from blood.

  Study EGAS00001000474

• WXS Tumor Samples Javelin head and neck 100

  We performed Whole Exome (WXS) and RNASeq sequencing on samples obtained from the phase 3 randomized, double-blinded, placebo-controlled study in patients with locally advanced squamous cell carcinoma of the head and neck JAVELIN Head and Neck 100 (NCT02952586). There are 471 WXS Tumor samples and 346 RNASeq tumor samples. All tumor samples have matching normal samples.

  Dataset EGAD00001011680

• Javelin head and neck 100

  We performed Whole Exome (WXS) and RNASeq sequencing on samples obtained from the phase 3 randomized, double-blinded, placebo-controlled study in patients with locally advanced squamous cell carcinoma of the head and neck JAVELIN Head and Neck 100 (NCT02952586). There are 471 WXS Tumor samples and 346 RNASeq tumor samples. All tumor samples have matching normal samples.

  Dataset EGAD00001011290

• RNAseq before and after cold pressor test

  The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken for RNA-sequencing. Files were processed and quantified with kallisto v0.42.5 using the human reference transcriptome (Gencode Release 28). Countdata was rlog-transformed.

  Dataset EGAD00001009649

• Dataset on keratinocytic gene expression pattern in Hidradenitis suppurativa

  Human skin samples were obtained from HS patients after informed consent (Ethical vote, University of Würzburg; No. 306/12). Lesional and perilesional were taken and epidermis and dermis separated. Isolated epidermal keratinocytes were further processed for RNA isolation. mRNA was extracted from five pairwise-matched lesional and perilesional epidermal HS pellets and RNA sequencing was performed.

  Dataset EGAD00001008005

• Whole genome bisufite sequencing for smoking and non-smoking mother-child pairs

  WGBS data of whole blood samples from smoking and non-smoking mothers and their children at gestation/birth and follow-up years.

  Dataset EGAD00001000366

• 10X Chromium 5' scRNA, scTCR and scBCR sequencing of pre- and on-treatment HNSCC biopsy samples

  We performed 10X Chromium 5' scRNA (n=50), scTCR (n=48) and scBCR (n=49) sequencing of pre- and on-treatment HNSCC biopsy samples.

  Dataset EGAD50000000056

• Cohort A germline exome sequencing

  Cohort A includes glioma tumors of varied grading and pathology from male and female individuals. Germline DNA was isolated from whole blood.

  Study EGAS50000000952

• Nanopore whole-genome sequencing of human sarcomas

  We performed single and multi-region nanopore whole-genome sequencing on human sarcoma samples from adult and paediatric patients.

  Study EGAS50000000651

• To determine the transcriptional profiles of Ovarian carcinomas (UW cohort)

  Specific BRCA and immune configurations determine optimal response to platinum-based chemotherapy in triple negative breast and ovarian carcinomas (UW_OvCa_RNAseq)

  Study EGAS00001006012

• scRNA-seq of monocultures and co-cultures of PDAC-PDOs and CAFs

  scRNA-seq of monocultures and co-cultures of patient-derived PDAC organoids and matched CAFs. 3 sample sets per patient.

  Dataset EGAD00001009655

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): COVID-19 Testing and Vaccination Social Network Diffusion for Diverse Criminal Legal Involved Communities

  This RADx-UP Phase II proposal, "Social network diffusion of COVID-19 prevention for diverse Criminal Legal Involved Communities", will implement a situation appropriate COVID-19 testing and vaccination social network diffusion intervention - C3 - building upon RADx-UP Phase I lessons and successful social network prevention interventions developed previously by the research team. C3 Criminal Legal Involved (CLI) populations encompass those non-incarcerated who have experienced recent arrest, incarceration, probation, parole or diversion programs such as drug courts. While increases in COVID-19 testing have been observed among this group, there remain members with limited testing history as well as individuals who are vaccine hesitant. COVID-19 prevention messaging can no longer be simplified to "everyone test and/or everyone vaccinate" as testing and vaccination decisions among community members are sensitive to personal histories (i.e., prior infection), local infection rates (i.e., low rates) and testing/vaccination availability. As COVID-19 prevention efforts have become more complicated (i.e., test if exposed), people tend to focus on the messenger, and particularly those that are close to them. Personal connections and communications within existing personal network structures, such as families, friends and other trusted acquaintances represent the cornerstone to increase situation appropriate testing and overcoming COVID-19 vaccine hesitancy. C3 builds upon RADx-UP I, by using a network diffusion approach facilitated through motivational interviewing purposefully geared to mobilize one's own organic social network to increase context appropriate testing and vaccine uptake. Through this process we will maximize the primary benefit and impact of this type of intervention which also has the intended effect of increasing likelihood that the messenger themselves will undergo the same behavior change that they have been trained to promote. We will leverage infrastructure developed in RADx-UP Phase I, which includes 4 high-impact sites across the Central US from Phase I: Baton Rouge LA, Little Rock AR, Indianapolis IN, and Chicago IL. We will utilize established engagement efforts already in place and continue to fully integrate communities in the strategic application of the intervention. We will use the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to guide implementation. C3 aims to: Aim 1a. Test the efficacy (3-month situation appropriate testing or vaccination) of a network diffusion intervention (C3) versus an existing COVID-19 testing and vaccine linkage to care intervention among: 1) primary study participants (primary outcome); and 2) secondary study participants connected to primary participants (secondary outcome) using a RCT design. Aim 1b. Explore the mechanisms for differential intervention effects at the individual and network-level that may increase situation appropriate testing and/or vaccination uptake. Aim 2. Examine key RE-AIM components in real time tied to the implementation of the network diffusion intervention (C3).

  Study phs003234

• Genetic Epidemiology of Chronic Lymphocytic Leukemia

  Chronic lymphocytic leukemia (CLL) is a subtype of B-cell lymphoproliferative disorders (LPD), and is the most common form of adult leukemia in Caucasians in the United States. Small lymphocytic lymphoma (SLL) is also a B-cell LPD and is typically considered to be the same disease as CLL, based on pathology. We consider CLL and SLL as the same disease entity, and hereafter refer to both simply as "CLL". Using genealogical databases and cancer records, the familial clustering for CLL is one of the strongest for all cancer sites, strongly implicating germline genetic risk. We ascertained CLL cases and controls for a genomewide association study (GWAS) that was undertaken as part of the International Lymphoma Epidemiology (InterLymph) consortium GWAS. Some CLL cases are also part of extended high-risk CLLpedigrees.

  Study phs001568

• Therapy-Induced APOBEC3A Drives Evolution of Resistance to Targeted Therapies in Non-Small Cell Lung Cancer

  The purpose of this study was to identify mechanisms of resistance and associated mutational signatures in non-small cell lung cancers (NSCLCs) treated with targeted therapies. Whole genome sequencing (WGS) and whole exome sequencing (WES) were performed on tumor tissue or cell lines derived from oncogene-driven NSCLCs before and after treatments with tyrosine kinase inhibitors. Somatic mutations were called and mutational signature analysis was performed, revealing enrichment of APOBEC mutational signatures mutational signatures in post-treatment tumors after the development to resistance to targeted therapies. The cohort includes WGS and WES data of tumor and normal tissues from patients with oncogene-driven NSCLCs harboring EGFR mutations, ALK fusions or NTRK1 fusions, who were treated with molecularly targeted therapies that target these oncogenes.

  Study phs003256

• Health Professionals Follow-Up Study

  Health Professionals Follow-up Study (HPFS) is a prospective cohort study of men designed to evaluate hypotheses about men’s health related to diet and lifestyle to the incidence of serious illnesses, such as cancer, heart disease, and other vascular diseases. It consisted of 51,529 U.S. male health professionals who were 40-75 years old at baseline in 1986 and completed a mailed six-page baseline questionnaire. Information on age, height and weight, ancestry, medications, disease history, physical activity, lifestyle factors, and diet were gathered, with follow-up questionnaires sent biennially to update information and record health outcomes with every four years to update their diet. This datafile includes responses to the 2016 questionnaire, which is available at: https://cdn1.sph.harvard.edu/wp-content/uploads/sites/2471/2017/09/16L.pdf

  Study phs002460

• DNA Methylation Analysis of Peripheral Blood Cells from Siblings Discordant for ASD

  Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental influencing and commonly is studied by examining dynamic methylation changes to the DNA. We have screened a total of 78 autistic boys and their fathers by this method in 807 genes and find 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. We propose to confirm these exciting data in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism.

  Study phs000619

• AACR Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE)

  AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pancancer registry of real-world data assembled through data sharing between 19 leading international cancer centers with the goal of improving clinical decision-making. The registry leverages ongoing clinical sequencing efforts (CLIA/ISO-certified) at participating cancer centers by pooling their data to create a novel, open-access registry to serve as an evidence base for the entire cancer community. Genomic and baseline clinical data from more than 70,000 tumors is accessible through the efforts of our strategic and technical partners, Sage Bionetworks and cBioPortal. The consortium and its activities are driven by openness, transparency, and inclusion to ensure that the project output remains accessible to the global cancer research community and ultimately benefits patients.

  Study phs001337

• IGNITE: Implementing GeNomics In practice: Genomic Medicine Implementation - The Personalized Medicine Program

  IGNITE is an NIH-funded network dedicated to supporting the implementation of genomics in healthcare. IGNITE was created to enhance the use of genomic medicine by supporting the development of methods for incorporating genomic information into clinical care and exploration of the methods for effective implementation, diffusion and sustainability in diverse clinical settings. As part of the IGNITE network, the University of Florida Health Personalized Medicine Program partners with health professionals and patients at UF Health and across the state to develop, implement, study and refine methods that allow genetic information to be used as a routine part of patient care. The program's initial focus is on pharmacogenetics. We also aimed to develop and implement innovative genomic medicine educational programs for health-care providers, health professions students, patients.

  Study phs001978

• National Sleep Research Resource (NSRR): Hispanic Community Health Study/Study of Latinos

  The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH) contributed to the first phase of the project. Raw polysomnography data are available from the HCHS/SOL Baseline visit and raw actigraphy data are available from the Sueño Ancillary visit. Primary HCHS/SOL data can be requested through dbGaP phs000810 Hispanic Community Health Study /Study of Latinos (HCHS/SOL).

  Study phs003543

• Spatiotemporal single-cell analysis reveals a time-dependent immunological modulation by multi-fractionated radiotherapy in esophageal cancer

  Description Here, by integrative spatial and single-cell analyses using spatial transcriptome (VISIUM) and single-cell RNA sequencing (scRNA-seq), we examined the spatiotemporal dynamics of immune-response in the tumor microenvironment of esophageal squamous cell carcinoma (ESCC) before, during and after RT. The comprehensive single-cell analyses demonstrated the infiltration of immune cells into tumor with the dynamic change of immune-stimulatory and -suppressive gene expression after RT. ScRNA-seq analysis uncovered the time- and cell-type-dependent alteration of gene expression profile from during to after RT. This datasets in the present study will provide the information of RT-induced gene signature to seek an appropriate target of personalized immunotherapy combined with radiotherapy and of determining the timing of the combination therapy.

  Study JGAS000712

• An allele-resolved nanopore-guided tour of the human placental methylome

  The placenta is a temporary organ present during pregnancy that is responsible for coordinating all aspects of pregnancy between the mother and fetus. It has a distinct epigenetic, transcriptomic, and mutational landscape with low levels of methylation, high numbers of transcribed loci, and a high mutational burden relative to somatic tissues. We present this landscape through the application of nanopore sequencing technology to provide a more comprehensive picture of female placental genomics and methylomics along with integrated haplotype-resolved transcriptomic analyses across eight trios. Whole genome sequencing of trios allows robust phasing, permitting comprehensive genome-wide investigation of parent-of-origin methylation and transcription. This enhanced view facilitates identifications of many new differentially methylated regions (DMRs), both conserved and differing between individuals, as well as novel imprinted genes.

  Study EGAS50000001301

• High-coverage whole exome sequence in non-TRU-type lung adenocarcinomas

  In order to elucidate the key genetic events in non-TRU-type lung cancer, we selected 43 non-TRU-type lung adenocarcinomas and performed a whole exome sequence and RNA-seq analysis using a next-generation sequencer. The results of the analysis identified mutations in TP53, KRAS and NKX2-1 as the top three significantly mutated genes, while the EGFR mutation was rare in this cohort. Eight NKX2-1 mutations (5 frameshift, 2 nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1 mutations (missense and frameshift). All NKX2-1 mutants were transcriptionally inactive in reporter assays. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1 mutations (5 cases), while 1 enteric and 1 acinar adenocarcinoma harbored the NKX2-1 mutation.

  Study JGAS000105

• Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma

  We conducted a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322) and assessed clinical responses and immune correlates. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST overall response rate 73%, pathologic complete response rate 45%) but substantial toxicity (73% grade 3 treatment related adverse events), whereas treatment with nivolumab monotherapy yielded modest responses (RECIST overall response rate 25%, pathologic complete response rate 25%) and low toxicity (8% grade 3 treatment related adverse events). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. Mutational load was also higher in responders to therapy.

  Study EGAS00001003178

• ICGC PedBrain: Deep-sequencing of childhood brain tumors.

  Brain tumors constitute the childhood tumors with the highest mortality rates and survival is often associated with severe long-term sequelae due to intensive multimodal treatment regimens. Thus, the PedBrainTumor network aims at the identification of robust biomarkers for clinical management and novel molecular targets for therapeutic interventions. Using massively parallel whole-genome sequencing, and transcriptome and methylome sequencing for subsets of cases, we aim to decipher the molecular causes of medulloblastoma as well as low-grade astrocytoma, and to identify markers to stratify patients for specialized treatment. As the PedBrain network is affiliated with clinical trials in medulloblastoma and pilocytic astrocytoma, validation cohorts for the translation of key findings into clinical settings are readily available.

  Study EGAS00001000215

• Circulating cell-free DNA analysis in Small Cell Lung Cancer

  Small cell lung cancer (SCLC) accounts for ~250,000 deaths worldwide each year. Acquisition of adequate tumour biopsies is challenging and liquid biopsies present the best option for patient stratification and response monitoring. We present genome-wide and targeted plasma DNA sequencing data that identifies tumour related changes in 91% of limited (LS-SCLC) and 100% of extensive stage (ES-SCLC) patients. Parallel analysis of circulating tumour cells (CTCs, by CellSearch) based on ≥ 1 CTC/7.5ml blood increased tumour detection frequencies to 98% patients (95% for LS-SCLC) where CTC count and plasma DNA readouts correlated with disease stage and overall survival (OS). Targeted plasma DNA sequencing identified potential therapeutic targets in >50% of patients. This approach will support trials of targeted therapies where improved patients outcomes are urgently required.

  Study EGAS00001003110

• 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/

  Study EGAS00001001182

• Comprehensive Transcriptional Analysis of Early Stage Urothelial Carcinoma using whole transcriptome sequencing

  The expression profile and sequence variants of 476 early stage urothelial carcinoma were studied using whole transcriptome sequencing. RNA-Seq libraries were prepared by Ribo-Zero treatment of total-RNA followed by library preparation using ScriptSeq (both Epicentre/Illumina). RNA-Seq libraries were paired-end sequenced (2x 101 bp) on Illumina HiSeq 2000 and the resulting fastq files were processed using tools from the Genome Analysis Toolkit (GATK and from the Tuxedo suite. Access to the sequence data (mapped and un-mapped bam and vcf files), containing person identifying information, needs signature on a controlled access form, and can be accessed at The European Genome-phenome Archive (EGA) following request. An expression matrice of FPKM values are available without restriction at ArrayExpress (E-MTAB-4321).

  Study EGAS00001001236

• Relaxed selection during a recent human expansion

  To better understand and quantify the effect of a recent expansion process on the amount and pattern of mutation load, we screened the ascending genealogies of 3916 individuals from the CARTaGENE cohort (Awadalla et al. 2013) that were linked to the BALSAC genealogical database (http://balsac.uqac.ca/). Using stringent criteria on the quality of genealogical information, we selected (front) individuals whose ancestors were as close as possible to the front of the colonization of Quebec, and (core) individuals whose ancestors were as far as possible from the front. We then sequenced these 102 individuals at very high coverage (mean 89.5X, range 67X-128X) for 106.5 Mb of exomic and UTR regions and contrasted their genomic diversity to detect if sites with various degrees of conservation and deleteriousness had been differentially impacted by selection.

  Study EGAS00001001957

• Neuroblastoma tumor heterogeneity and cell plasticity (from PDX and cell lines)

  Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific core regulatory circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain to be defined. Here, we document a spontaneous plasticity between the noradrenergic and mesenchymal identities in a subset of cell lines. Strikingly, mesenchymal neuroblastoma cells revert to a noradrenergic phenotype in vivo. Consistently, tumor cells with a mesenchymal identity are detected in single-cell transcriptomic analyses of neuroblastoma tumors and PDX models. Our data also highlight neuroblastoma intra-tumor heterogeneity with the co-existence of distinct tumor populations, including sympathoblast-like and chromaffin-like cells suggesting that neuroblastoma cells arise from a common sympatho-adrenal progenitor.

  Study EGAS00001004781

• Upper respiratory microbiome of COVID-19 patients

  Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 microbiome studies by analyzing the upper respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19.

  Study EGAS00001004951

• Longitudinal monitoring of cell-free DNA methylation in ALK-positive non-small cell lung cancer patients

  Here, we performed genome-wide 5-mC profiling in plasma of metastatic ALK-rearranged non-small cell lung cancer (NSCLC) patients receiving tyrosine kinase inhibitor therapy. We established a strategy to identify ALK-specific 5-mC changes from cfDNA and demonstrated the suitability of the identified markers for cancer detection, prognosis and therapy monitoring. Longitudinal plasma samples (n = 79) of 21 ALK-positive NSCLC patients and 13 healthy donors were collected alongside 15 ALK-positive tumor tissue and 10 healthy lung tissue specimens. All plasma and tissue samples were analyzed by cell-free DNA methylation immunoprecipitation sequencing to generate genome-wide 5-mC profiles. Information on genomic alterations (i.e., somatic mutations/fusions and copy number alterations) determined in matched plasma samples were available from previous studies.

  Study EGAS00001006573

• Evolutionary landscape of clonal hematopoiesis in 3359 individuals from the general population

  This project contains longitudinal data for processed somatic variant calls and data on core phenotypic variables for 3359 community-based individuals ≥60 years, a sub-cohort of the population-based Lifelines cohort (167,729 participants). Cases with peripheral blood count abnormalities and population-based controls were included. Next-generation sequencing data were generated with a median time period of 43 months between baseline and follow-up visit. For 327 individuals a third visit sample was included. Error-corrected sequencing was performed using single-molecule tagged molecular inversion probes targeting 27 myeloid and lymphoid driver genes. The threshold for variant calling was set at ≥1% VAF and ≥10 consensus variant reads. Details on sample selection, sequencing technique, variant calling procedures and data curation are described (van Zeventer et al. 2023).

  Study EGAS00001007087

• SNP array data for the Milieu Intérieur cohort

  The Milieu Intérieur Consortium aims at identifying the environmental and genetic factors driving variation in innate and adaptive immune systems among healthy individuals. In the last four years, we combined standardized flow cytometric analysis of blood leukocytes, transcriptional profiles of whole blood after immune stimulation and genome-wide DNA genotyping in 1,000 healthy, unrelated donors of western European ancestry, to show that age, sex, as well as persistent infections and smoking, are the most important drivers of inter-individual differences in blood cell composition and transcriptional response to pathogens. The EGAS00001002460 study includes genotype data for 5,699,237 genotyped and imputed SNPs in the 816 healthy donors of the Milieu Intérieur cohort. Note that 184 of the 1,000 initial donors did not agree to share their data online.

  Study EGAS00001002460

• Comprehensive spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

  Although immunosuppressive and pro-metastatic functions of FAP+ Cancer-Associated Fibroblasts (CAF) are well-established, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate an integrative high-resolution map of breast cancer (BC), focusing particularly on the different subpopulations within inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are precisely localized within tumors. Consistent with their spatial organization, we identify DPP4- and YAP1-dependent mechanisms, by which cancer cells drive the transition of the detoxification-associated inflammatory FAP+ CAF cluster (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myofibroblasts (ECM-myCAF). In turn, ECM-myCAF polarize TREM2+ macrophages and regulatory NK cells to induce immunosuppressive EcoCellTypes. FAP+ CAF subpopulations accumulate differently depending on the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

  Study EGAS50000000220

• Longitudinal genome-wide analysis of progressive chronic lymphocytic leukemia under uniform front-line therapy of pentostatin, cyclophosphamide, and rituximab

  Samples from two-center prospective phase 2 clinical trail conducted at Ohio State University (Columbus, OH) and Mayo Clinic (Rochester, MN) were analyzed in 12 cases. All patients had progressive CLL as defined by National Cancer Institute (NCI) Working Group criteria. Patients provided written informed consent for correlative studies according to the Declaration of Helsinki on an institutional review board approved protocol for the collection and use of samples for research purposes from both participating institutions. Eligible patients received a regimen consisting of pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) provided intravenously on day 1 of a 21-day cycle for a maximum of 6 cycles. Responses were assessed by NCI Working Group criteria and included a bone marrow evaluation and two-color flow cytometry 2 months after completion of therapy. Peripheral blood samples from these patients collected longitudinally before (Pre-Baseline), at (Baseline) and after therapy (Relapse) were analyzed for genomic heterogeneity and clonal complexity by high throughput Exome sequencing.

  Study phs000794

• A Pilot Study of Rapid Autopsy and Procurement of Tissue in Thoracic Malignancy Cancer Patients to Investigate Tumor Heterogeneity

  Integrated proteo-genomics studies to characterize tumor heterogeneity of metastatic lung adenocarcinoma and thymic carcinoma are lacking. We carried out whole exome sequencing, RNA sequencing, copy number estimation and mass spectrometry-based proteomics of 40 tumors from five rapid/warm autopsy patients. We found highly variable mutational heterogeneity that was largely driven by APOBEC-mutagenesis with the expression of APOBEC3B (Gene ID: 9582) and APOBEC3A_B (Gene ID: 100913187) due to underlying APOBEC3 region germline variants as the likely mediating mechanism. APOBEC3A_B expression was associated with increased immune tumor microenvironment and CD274 (Gene ID: 29126) expression while smoking was associated with increased APOBEC-mutagenesis in TP53 (Gene ID: 7157) mutant tumors with high APOBEC3B expression. Heterogeneity at the level of the transcriptome and proteome occurred in association with copy number heterogeneity, not APOBEC-induced mutational heterogeneity. Arm and focal copy number alterations (CNAs) occurred as an evolutionarily late event in a subset of patients, with corresponding changes in the transcriptome and proteome, implicating CNAs as a driving force of heterogeneity in the evolution of metastatic disease.

  Study phs001432

• The Immune Microenvironment Shapes Transcriptional and Genetic Heterogeneity in Chronic Lymphocytic Leukemia

  Tumor microenvironment (TME) and somatic mutations drive progression of chronic lymphocytic leukemia (CLL). Integrated bulk and single-cell RNA sequencing (RNA-seq) of paired peripheral blood (PB) and lymph node (LN) samples from patients with treatment-naïve CLL showed upregulation of oncogenic processes in LN attributable to a minor population of activated tumor cells. A 10-gene tumor signature derived from this population was positively correlated with activated CD4+ T cells and M2 macrophages in the TME. Whole exome sequencing of paired PB and LN samples showed subclonal expansion in LN in some patients. In remaining patients with clonal stability between PB and LN, a T-cell inflamed TME was detected by RNA-seq. These data connect the TME with molecular events in the evolution of CLL.This cohort was later augmented with whole exome sequencing for 15 additional CLL samples. In an integrative analysis of genetic, transcriptomic, and epigenetic data, including the data from this study, we built new models to improve CLL patient prognostication.

  Study phs002297

• BPH Tissues for Cell Culture and Analysis - Spatial Transcriptomics Identifies Candidate Stromal Drivers of Benign Prostatic Hyperplasia

  The study goal was to apply spatial transcriptomics to identify candidate stromal drivers of benign prostatic hyperplasia (BPH). Laser microdissection (LCM) with RNA-seq of the stroma adjacent to hyperplastic and budding BPH ducts identified secreted factors including IGF1 and CXCL13. Single‐cell RNA sequencing (scRNA‐seq) revealed their co-expression from BPH fibroblasts. Additional studies sought to define similarities to embryonic prostate development, as well as therapeutic applications. Subjects were those who underwent prostatectomy for prostate or bladder cancer, with concurrent BPH, and who consented to use of surplus tissue for research studies. LCM/RNA-seq studies included 5 patients, and scRNA-seq studies included 1 patient. Phenotypic data submitted to this study include patient age, sex, prostate size, and international prostate symptom score (IPSS). Sequencing was done on an Illumina NovaSeq 6000 (LCM/RNAseq) and Illumina HiSeq X-Ten (scRNA-seq). The data processing pipeline utilized Kallisto (LCM/RNA-seq) and Cell Ranger (scRNA-seq). Data submitted are raw sequencing (Fastq) files.

  Study phs003477

• Gabriella Miller Kids First Pediatric Research Project in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects

  This study involves a cohort of 400 individuals and family members with Cornelia de Lange Syndrome (CdLS) and CdLS-like phenotypes for which a molecular etiology has not yet been established. CdLS is a developmental disorder characterized by development delays, cognitive impairment, short stature, hearing loss, specific facial features, and structural birth defects such as differences of the limbs, heart, kidneys, and GI tract. Our approach to tease out genetic contributions to birth defects has been to identify the underlying causes of syndromic birth defects which are often Mendelian in nature and therefore lend themselves more readily to genetic causal identification. Once identified, these genetic causes of syndromic forms of birth defects can be leveraged to understand the genetic contributions to isolated birth defects seen in constellation in syndromes such as CdLS. This work will lead to the identification of genes critical in human embryonic development, provide novel insights into transcriptional regulation and help to identify genetic causes and candidate genes for isolated birth defects seen in constellation in similar diagnoses.

  Study phs002174

• Cancer cell and tumor microenvironment biomarkers associated with disease-free survival with adjuvant nivolumab in the phase 3 CheckMate 274 trial

  In the CheckMate 274 trial, adjuvant nivolumab versus placebo demonstrated an improvement in the primary endpoint of disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma after radical resection. An extensive analysis of tumor biomarkers, including their associations with DFS, was performed. Analysis of genome-wide differential gene expression and known gene signatures found that immune-related genes and pathways, in particular an IFNγ signature, were predictive of DFS in nivolumab-treated patients. Predictive and prognostic associations, respectively, were found for tumor-infiltrating CD4 and CD8 T cells. Analysis of a composite predictive model suggested that CD4 gene expression and tumor cell PD-L1 expression had the greatest contributions to predicting outcomes in nivolumab-treated patients. These results reinforce recent studies establishing the importance of biomarkers of adaptive immunity, and in particular CD4 T cells, in influencing response to PD-1/PD-L1 blockade and establish the potential predictive rather than solely prognostic nature of such findings.

  Study EGAS50000000560

• Copy number variations and fragmentation features in cell-free DNA predict response in advanced non-small cell lung cancer patients under anti-PD-(L)1 therapy

  Anti-PD-(L)1 therapy is routinely used in metastatic NSCLC. However, response rates vary and biomarkers predicting treatment efficacy are lacking. Liquid biopsies allow monitoring of residual disease during therapy. Residual circulating tumor DNA (ctDNA) after therapy represents a predictive marker for adverse outcome. Here, we assessed copy number variations (CNVs) in serial plasma samples of NSCLC patients receiving PD-(L)1 blockade. We profiled CNV and fragmentation features in 118 plasma samples of advanced NSCLC patients by low-coverage whole genome sequencing taken at baseline, after four therapy cycles and at disease progression. CNVs and fragment features (i.e., fragment length, end motifs, position) were significantly altered in patients compared to healthy donors. Furthermore, fragment length changes at baseline and residual CNVs after four therapy cycles correlated with short progression-free survival. Our results highlight the suitability of plasma-based CNV and fragment analysis for disease monitoring and as a predictive marker for response duration in NSCLC patients under anti-PD-(L)1 therapy.

  Study EGAS50000000441