Search Results - EGA European Genome-Phenome Archive

RNA-seq analysis of metastatic prostate cancer solid tumor biopsies

The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)–targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival.

Study EGAS00001006369

scRNA-seq and scTCR-seq data IMCISION

We performed single cell RNA and TCR sequencing (10x Genomics) on immune infiltrates (CD45+ cells) from 18 HNSCC patients enrolled in the IMCISION trial (Vos et al. 2021). Viable immune cells were isolated from pre-treatment and on-treatment primary tumor biopsies of 10 patients responding (1 partial pathological response and 9 major pathological responses) and 7 patients non-responding to anti-PD-1 and anti-CTLA4 combination immunotherapy. One patient treated with anti-PD-1 monotherapy (1 major pathological response) was included in the dataset.

Study EGAS00001007368

DAC for Central African ancient demography processes NGS dataset

Title DAC Ancient tree-topologies and gene-flow processes among human lineages in Africa Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Short description The Data Access Committee for acess to genotype and sample information used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa" by Gwenna Breton et al. 2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. DNA samples from individuals were collected with the subjects’ informed consent following the Declaration of Helsinki guidelines and approved by the following Ethics committees: Institut de Recherche pour le Développement (IRD, France); Cameroon Ministry of Scientific Research and Technology; Central African Republic Ministère de l’Enseignement Supérieur et de la Recherche Scientifique; France Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (Comité de Protection des Personnes DC-2016-2740); French Commission Nationale Informatique et Liberté CNIL (declaration n°1972648); Uganda National Council for Science and Technology; Institutional Review Board of the University of Chicago Biological Sciences Division and the Pritzker School of Medicine University of Chicago Hospitals (protocol number 16986A); Committee for the Protection of Human Subjects of the Trustees of Dartmouth College and the Dartmouth-Hitchcock Medical Center (protocol number 22410); Human Research Ethics Committee (Medical) at the University of the Witwatersrand, Johannesburg (Protocol Numbers: M980553, M050902, M090576, M10270, M180654); Working Group of Indigenous Minorities in Southern Africa (WIMSA); South African San Council (SASC); and the Swedish Ethical Review Authority (Dnr 2019-05174). Requests for accessing all or part of the Central African data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), should be addressed to the DAC providing: 1) Data can only be used to explore human genetic evolution, evolutionary ecology and population history 2) The research institution where data will be stored and were analyses will be conducted. 3) The detailed coordinates of the researcher responsible for data storage and analyses. 4) A description (max 20 sentences) of the scientific finality and context of the project and classes of methodological analyses that will be performed to achieve it using the requested data. 5) When applicable, mention also other previously published data sets that will be used jointly with the requested datas et For accessing any or all the Central African genetic data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), the requester hereby ensures that: 1) Individual donor privacy should be respected at all times. Data cannot be made publicly available under any circumstances. 2) Data cannot be shared nor transferred to a third party without re-applying for eGA access to the DAC. 3) No direct or indirect commercial use of the data can be made 4) No individual medical genetics or disease diagnostics can be performed with the data 5) No medical or legal forensic investigations can be conducted with the data 6) No genealogical research can be conducted with the data (e.g. no paternity nor maternity testing, no genetic identification, no search of relatives using other datasets) 7) Appropriate citation of the article and data set used for any scientific communication using the data 8) Data is destroyed after the completion of the project. Any further re-use of the data is subject to a novel application to the DAC.

Dac EGAC50000000447

Oxford Nanopore WGS

A total of 20 individuals, were analyzed using Oxford Nanopore Technologies long-read sequencing. Each individual was sequenced on one PromethION flow-cell, providing approximately 25-30X coverage of the genome. The data is deposited as nanopore BAM files with methylation information included.

Dataset EGAD50000000573

LRS - episignature samples

This dataset contains 22 long-read WGS fastq.gz files sequenced ONT PromethION. In total the dataset includes 20 individuals, for all of them sequencing starting from blood was performed, and for one of the samples sequencing from urine and from the buccal swab was also included. In all the samples methylation calls are included in the fastq file.

Dataset EGAD50000001000

LuCaP cell line RNA-seq

RNA-seq of LuCaP 189.4 cell line. Treatment with DCC DMSO (n=3 replicates) or 1nm R1881 (n=3 replicates). All 6 samples were sequenced using cDNA oligo-dT using paired-end reads on Illumina NovaSeq 6000. Each sample has 2 fastq files, one for the forward and reverse read, respectively.

Dataset EGAD50000001344

WGS data of paediatric B-other B cell acute lymphoblastic leukemia (set6)

The dataset includes FASTQ and CRAM files from diagnostic and matched remission (control) samples of one B-other ALL patients (ALLK-138). Sequencing library was made using Novogene NGS DNA Library Prep Set. Both diagnostic (90x) and remission (30x) samples were sequenced using NovaSeqX Plus.

Dataset EGAD50000002161

Exome Sequencing of Spanish Patients with rare genetic diseases.

Whole Exome sequencing of a set of Spanish patients suffering rare genetic diseases. The set consists of 3 patients, two were diagnosed with Aniridia (ANI-0006 and ANI-0023) and another one was diagnosed with Retinitis Pigmentosa (RP-0247).

Dataset EGAD00001005498

CTCF ChIP-sequencing data for Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

This dataset contains CTCF ChIP-sequencing data from seven samples (six tumor samples and one tumor derived cell line). Following library amplification, DNA fragments were sequenced using Illumina HiSeq 2000 paired-end sequencing resulting in 14 FASTQ files.

Dataset EGAD00001008806

Whole Exome Sequencing of a Chinese Cataract Girl

Whole exome sequencing of a Chinese girl with congenital cataract. The dataset contains one sample with two fastq files. The novel PAX6 mutation (c.221G>A) is associated with congenital cataract, and the WFS1 mutation (c.2070_2079del) interactively aggravates this process.

Dataset EGAD00001008267

Exome sequencing of synchronous colorectal cancers

The data consists of 47 exome-sequenced synchronous colorectal cancers from 23 patients. The exomes of corresponding normal samples were used to remove germline variants. All patients are Finnish (white Caucasian). All except one patient (sync_11 who belongs to a LS family) were assumed sporadic. The sequence data was produced with Illumina HiSeq 4000.

Dataset EGAD00001004884

Whole-exome sequencing of additional thyroid disease cases (2018-08-13)

Whole-exome sequencing of a cohort of families (probands and affected/unaffected relatives) suffering from one of two rare thyroid disorders: congenital hypothyroidism (CH) and resistance to thyroid hormone (RTH). . This dataset contains all the data available for this study on 2018-08-13.

Dataset EGAD00001004293

MCO colorectal cancer genomics at UNSW

This dataset contains DNA sequencing data from 95 colorectal cancer and matched-normal samples. The dataset contains targeted deep sequencing of selected regulatory elements in 95 cancer and matched-normal samples, and data for one sample that was additionally whole-genome sequenced (cancer and matched-normal).

Dataset EGAD00001004582

Whole-exome sequencing of additional thyroid disease cases (2017-05-11)

Whole-exome sequencing of a cohort of families (probands and affected/unaffected relatives) suffering from one of two rare thyroid disorders: congenital hypothyroidism (CH) and resistance to thyroid hormone (RTH). This dataset contains all the data available for this study on 2017-05-11.

Dataset EGAD00001003331

Drug Signatures for Prediction and Mitigation of Toxicity

The overall goal of the drug signatures for prediction and mitigation of toxicity study is to use genomic and proteomic high-throughput measurements as the basis for computational analysis that integrates network analyses with structural constraints and dynamical models in multiple cell types to identify signatures that predict toxicity induced by 55 FDA-approved chemotherapeutic drugs and potential mitigation of this toxicity. Specifically, we have recruited and pre-screened healthy individuals to be included in our study. Ninety six male and female individuals that satisfied the initial pre-screening for the study and their sex, age, race/ethnicity recorded through an enrollment questionnaire were consented. Eighty five underwent a formal and thorough medical health screening. The evaluation involved assessment of all inclusion and exclusion criteria, a full medical history, measurement of weight, height, waist and hip circumference, heart rate, blood pressure, respiratory rate, and oxygen saturation, a physical exam and an electrocardiograph (ECG). Blood was drawn for analysis of clinical relevant parameters. A pregnancy test was included for female participants. All blood draws and pregnancy tests were sent to a certified clinical laboratory for clinical analysis. Of the 85 subjects that were screened 42 (48.3%) were deemed eligible for final inclusion. Of these 42, one declined to undergo skin biopsy and/or venesection and one subject didn’t show up for the scheduled biopsy, leaving 40 clinically healthy subjects on which a skin biopsy and venesection was performed. Fibroblast lines were established from the skin biopsies. Induced pluripotent cells (iPSC) were generated from the established fibroblast lines of these 40 clinically healthy racially diverse male and female study participants who ranged in age from 22 and 61 years through reprogramming using either the mRNA or Sendai-virus methods. One clone from each of the 40 iPSC line was fully characterized for normal karyotype, short-tandem repeat matching to the original fibroblast line (authentication), pluripotency by select pluripotent marker expression via immunocytochemistry and by mRNAseq-based PluriTest analysis, and whole-genome sequencing.

Study phs002088

Temporal Lobe Epilepsy and Retrotransposons

Idiopathic (cryptogenic) epilepsy is a common, chronic group of brain disorders, affecting 1-2% of the US population, creating a significant public health problem because of the associated morbidity and mortality. One subtype of this complex group of brain disorders, temporal lobe epilepsy (TLE), is particularly burdensome, because a substantial fraction of patients do not respond to anticonvulsant medications. If the seizure focus can be localized by imaging and/or EEG, the TLE patient often elects to have a partial resection of the affected temporal lobe, because they have daily seizures, despite multiple pharmacotherapy regimens. Although genetic risk is thought to play a role in TLE, identification of common risk alleles has had limited success. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that developing neurons may accumulate de novo L1 insertions. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1s will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional de novo L1s occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to become an epileptic focus. This study leveraged CNS tissue (obtained at craniotomy) from patients with intractable TLE, who have undergone a therapeutic partial resection of one temporal lobe. Using fluorescence-assisted cell sorting of temporal lobe neuronal nuclei, followed by high-throughput sequencing and alignment to the reference genome, detection of de novo L1s will be done. In this manner, it is expected that de-novo intragenic L1s, contributing to idiopathic TLE, will be discovered.

Study phs002067

Genomic analysis of patient-derived xenograft models reveals intratumor-heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. Results: PDX models were successfully generated with similar histomorphology from all four molecular subtypes of EC and uterine carcinosarcomas. We also observed a wide range of inter-tumor and intra-tumor heterogeneity across different PDX lineages, however one arm of most PDX models recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease, however all lacked the HR deficiency genomic signature. Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

Study EGAS00001004666

Personalized Medicine Strategy for MPNSTs: Using Precision Oncology on PDOX Models to Inform Tumor Boards

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are a heterogeneous group of aggressive soft tissue sarcomas with poor prognosis. Currently there is a lack of effective treatments for MPNSTs. Here, we propose a personalized medicine approach that integrates a precision oncology strategy guided by MPNST genomic analysis, with a functional validation of treatment response in an orthotopic xenograft model (PDOX) derived from the same MPNST. Methods: Comprehensive whole genome sequencing analysis was performed in primary MPNSTs, relapses and (in one case) metastases, following disease progression in two independent individuals. Matched MPNST PDOX models were generated by orthotopically implanting tumor fragments near the sciatic nerve of immunodeficient mice. Candidate targeted combination therapies were prioritized based on genomic alterations and tested in vivo in the PDOX models. Results: The feasibility of the developed strategy is illustrated for two MPNST patients, one Neurofibromatosis type 1 (NF1) individual that developed two independent MPNSTs and another sporadic MPNST case with multiple metastatic relapses. Genomic analysis revealed a remarkable degree of genomic stability across primary MPNSTs and their successive relapses in each patient, and even metastases in one individual. While based on a small number of cases requiringing additional analyses, this finding aligns with previous evidence suggesting a fair genomic conservation throughout tumor evolution. This stability supports the identification of consistent therapeutic vulnerabilities throughout disease progression. Among the therapies tested, co-treatment of MEK inhibitor (MEKi) plus bromodomain inhibitor (BETi) elicited the highest antitumor activity, resulting in approximately 60% tumor volume reduction in the sporadic MPNST PDOX model, whose patient has been receiving this therapy for eight months with sustained remission. Conclusions: This study demonstrates the feasibility and clinical utility of integrating genomic-driven precision oncology with PDOX-based functional testing for MPNSTs. This strategy may support molecular tumor boards (MTBs) in their treatment decisions. The observed genomic stability supports the use of longitudinal tumor profiling to guide treatment, and the success of MEKi+BETi highlights its potential as a combination therapy for MPNSTs.

Study EGAS50000001502

Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy

BACKGROUND: Our understanding of T cell evolution under checkpoint inhibitors (CPI) is still incomplete, restraining the achievement of full benefit from CPI.OBJECTIVES: We studied peripheral T cell turnover and evolution and their prognostic value after 3weeks on treatment with CPI (one cycle) analysing T cell receptor-β (TCR) sequences in plasma cell-free DNA (cfDNA) and PBMC, and performing a phenotypic analysis of peripheral T cell subsets.RESULTS: Peripheral T cell turnover and TCR repertoire dynamics correlated with response. Additionally, the cfDNA TCR repertoire reorganisation fingerprint correlated with the expansion of an immune-effector subset of peripheral T cells that predicted treatment response and identified the patients with longer overall survival.CONCLUSIONS: Here we show that prognostic changes in peripheral T cells occur within 3 weeks of commencing CPI treatment. This dynamic immune-awakening informs on the immune-system reorganization can be monitored using minimally invasive liquid biopsies.

Study EGAS00001004043

ELLIPSE Prostate Cancer Meta-Analysis and Genotyping

The ELLIPSE Consortium is an international effort to discover risk loci for prostate cancer. It includes the meta-analysis of existing GWAS data as well as novel GWAS, exome, and iCOGS genotyping. The GWAS meta-analysis includes the following cases and controls from studies of European ancestry: UK GWAS stage 1 (Illumina Infinium HumanHap 550 Array: 1854 cases and 1894 controls), UK GWAS stage 2 (Illumina iSELECT: 3706 cases and 3884 controls), CAPS1 (Affymetrix GeneChip 500K: 474 cases and 482 controls), CAPS2 (Affymetrix GeneChip 5.0K: 1458 cases and 512 controls), BPC3 (Illumina Human610 Illumina: 2068 cases and 3011 controls), PEGASUS (HumanOmni2.5: 4600 cases and 2941 controls). The OMNI 2.5M genotyping was conducted for 977 prostate cancer cases from UKGPCS. The Exome SNP array genotyping was conducted for 4741 subjects from UKGPCS. The iCOGs genotyping was conducted for 10366 subjects which includes the Multiethnic Cohort (n=1648) and UKGPCS (n=8718). Below is a description of each study that contributed to the meta-analysis of men of European ancestry. Information about the studies that contributed to the multiethnic meta-analysis can be found on the associated study page and also in Conti et al (Nature Genetics, PMID:33398198).   UK GWAS Stage 1 (UK1) and Stage 2 (UK2): The UK Genetic Prostate Cancer Study (UKGPCS) was first established in 1993 and is the largest prostate cancer study of its kind in the UK, involving nearly 189 hospitals. We are based at The Institute of Cancer Research in Sutton, Surrey, and collaborate with the Royal Marsden NHS Foundation Trust. Our aim is to find genetic changes which are associated with prostate cancer risk. Our target is to recruit 26,000 gentlemen into the UKGPCS by 2017. Men are eligible to take part if they fit into at least one of the following groups: They have been diagnosed with prostate cancer at 60 years of age or under (up to their 61st birthday). They have been diagnosed with prostate cancer and a first, second or third degree relative where at least one of these men were diagnosed with prostate cancer at 65 years of age or under. They are affected and have 3 or more cases of prostate cancer on one side of their family. They are a prostate cancer patient at the Royal Marsden NHS Foundation Trust. We have to date recruited around 16,000 men on whom we have germline DNA and clinical data at diagnosis. The UK GWAS is based on genotyping of 541,129 SNPs in 1,854 individuals with clinically detected (non-PSA-screened) prostate cancer (cases) and 1,894 controls. 43,671 SNPs showing strong evidence of association in stage 1 were followed up by genotyping a further 3,268 cases and 3,366 controls from UK and Melbourne in stage2. CAPS1 and CAPS2: The CAPS (Cancer of the Prostate in Sweden) study represents a large Swedish population-based cancer study, comprising 3,161 cases and 2,149 controls, recruited between 2001 and 2003. Biopsy confirmed prostate cancer cases were identified and recruited from four out of six regional cancer registries in Sweden, diagnosed between July 2001 and October 2003. Clinical data including TNM stage, Gleason grade and PSA levels at time for diagnosis were retrieved through record linkage to the National Prostate Cancer Registry. Control subjects, who were recruited concurrently with case subjects, were randomly selected from the Swedish Population Registry and matched according to the expected age distribution of cases (groups of 5-year intervals) and geographic region. Whole blood was collected from all individuals for extraction of genomic DNA. A GWAS was conducted in two parts. In the first phase (CAPS1) 498 cases and 502 controls were genotyped, in the second phase 1,483 cases and 519 controls were genotyped. Genotyping was performed using the GeneChip Human Mapping 500K (CAPS1) and 5.0K (CAPS2) Array Set from Affymetrix (Santa Clara, CA). The National Cancer Institute Breast and Prostate Cancer Cohort Consortium, BPC3: BPC3 was a consortium of prospective cohort studies investigating genetic and gene-environmental risk factors for breast and prostate cancer. Each study selected cases and controls for this study as described below. The clinical criteria defining advanced prostate cancer (Gleason = 8 or stage C/D) were either obtained from medical records or cancer registries. The Gleason score source was either surgical specimens (radical prostatectomy or autopsy) or the diagnostic biopsy (needle biopsy or TURP). When multiple Gleason scores were available the surgical value was used. PLCO was removed from the analysis as the samples were included in the Pegasus GWAS described below. In total 2,473 advanced prostate cancer cases and 3,534 controls were included in the analysis following QC. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: ATBC was a randomized, placebo-controlled primary prevention trial to investigate whether α-tocopherol or ß-carotene supplementation reduced the incidence of lung or other cancers in male smokers. Between 1985 and 1988, 29,133 men ages 50 to 69 years were enrolled in the trial from Finland and randomized to supplementation (50 mg α-tocopherol, 20mg ß-carotene, or both) or placebo. Men with a prior history of cancer, other than non-melanoma skin cancer or carcinoma in situ, were excluded from participating. Incident cancer cases are identified through linkage with the Finnish Cancer Registry, which has ~100% ascertainment of cancer cases nationwide. Cases included 249 men diagnosed with advanced prostate cancer (Gleason = 8 or stage C/D) from 1985 to 2003 with DNA available. Controls were 1,271 men selected previously for a GWAS of lung cancer in ATBC without a diagnosis of prostate cancer. CPSII, Cancer Prevention Study II: CPSII is a cohort study started in 1982 to investigate the relationship between dietary, lifestyle and other etiologic factors and cancer mortality. Approximately 1.2 million men and women enrolled in the study from 50 states in the U.S. In 1992, a subset of these participants (n= ~184,000) were enrolled in the CPSII Nutrition Cohort to examine the relationship between dietary and other exposures and cancer incidence. Blood samples were drawn from approximately 39,376 members of the Nutritional Cohort from 1998 to 2001, and buccal cells were collected from 69,467 members from 2001 to 2002. Cancer cases are identified by self-report through follow-up questionnaires followed by verification through medical records and/or linkage to state cancer registries as well as death certificates. A total of 660 advanced prostate cancer cases (Gleason = 8 or stage III/IV) with a source of DNA were identified for this study. Controls were 660 men matched on ethnicity, date of birth, sample collection date and DNA type. EPIC, European Prospective Investigation into Cancer and Nutrition: EPIC is a prospective study designed to investigate both genetic and non-genetic risk factors for different forms of cancer. Study participants were almost all white Europeans. Approximately 500,000 individuals (150,000 men) in EPIC were recruited between 1992 and 2000, from 23 centers in 10 European countries. Overall approximately 400,000 subjects also provided a blood sample at recruitment. The methods of recruitment and details of the study design are described in detail elsewhere. In brief, study participants completed an extensive questionnaire on both dietary and nondietary data at recruitment. The present study includes subjects from advanced prostate cancer cases (Gleason = 8 or stage III/IV) matched to controls based on study center, length of follow-up, age at enrollment (± 6 months), fasting and time of day of blood collection (± 1 hour). The advanced prostate cancer subjects were from 8 of the 10 participating countries: Denmark, Germany, Greece, Italy, the Netherlands, Spain, Sweden and the United Kingdom (UK). France and Norway were not included in the current study because these cohorts only included female subjects. All participants gave written consent for the research and approval for the study was obtained from the ethical review board from all local institutions in the regions where participants had been recruited for the EPIC study. HPFS, Health Professionals Follow-up Study: HPFS began in 1986 and is an ongoing prospective cohort study of 51,529 United States male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians 40 to 75 years of age. The baseline questionnaire provided information on age, marital status, height and weight, ancestry, medications, smoking history, disease history, physical activity, and diet. At baseline the cohort was 97% white, 2% Asian American, and 1% African American. The median follow-up through 2005 was 10.5 years (range 2-19 years). Self-reported prostate cancer diagnoses were confirmed by obtaining medical and/or pathology records. Prostate cancer deaths are either reported by family members in response to follow-up questionnaires, discovered by the postal system, or the National Death Index. Questionnaires are sent every two years to surviving men to update exposure and medical history. In 1993 and 1994, a blood specimen was collected from 18,018 men without a prior diagnosis of cancer. Prostate cancer cases are matched to controls on birth year (+/-1) and ethnicity. Controls are selected from those who are cancer-free at the time of the case’s diagnosis, and had a prostate-specific antigen test after the date of blood draw.   MEC, Multiethnic Cohort: The Multiethnic Cohort Study is a population-based prospective cohort study that was initiated between 1993 and 1996 and includes subjects from various ethnic groups - African Americans and Latinos primarily from Californian (great Los Angeles area) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drivers’ license files were the primary sources used to identify study subjects in Hawaii and California. Additionally, in Hawaii, state voter’s registration files were used, and, in California, Health Care Financing Administration (HCFA) files were used to identify additional African American men. All participants (n=215,251) returned a 26-page self-administered baseline questionnaire that obtained general demographic, medical and risk factor information. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on stage and grade of disease are also obtained through the SEER registries. Blood sample collection in the MEC began in 1994 and targeted incident prostate cancer cases and a random sample of study participants to serve as controls for genetic analyses. PHS, Physicians Health Study:PHS was a randomized trial of aspirin and ß carotene for cardiovascular disease and cancer among 22,071 U.S. male physicians ages 40-84 years at randomization; none had a cancer diagnosis at baseline. The original trial ended, but the men are followed. From 1982 to 1984, blood samples were collected from 14,916 physicians before randomization. Participants are sent yearly questionnaires to ascertain endpoints. Whenever a physician reports cancer, we request permission to obtain the medical records, and cancers are confirmed by pathology report. We obtain death certificates and pertinent medical records for all deaths. Follow-up for nonfatal outcomes in PHS is over 97% complete, and for mortality, over 99%. PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial:PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen (PSA) annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 754 men diagnosed with advanced prostate cancer (Gleason = 8 or stage III/IV) from either arm of the trial. Of these cases, 317 were genotyped previously as part of Cancer Genetic Markers of Susceptibility (CGEMS), a GWAS for prostate cancer. Controls included 1,491 men without a diagnosis of prostate cancer from the screening arm of the PLCO trial. All subjects provided informed consent to participate in genetic etiology studies of cancer and other traits. This study was approved by the institutional review boards at the ten centers and the National Cancer Institute. PLCO was removed from the meta-analysis of the BPC3 studies as a consequence of PEGASUS below. PEGASUS, Prostate cancer Genome-wide Association Study of Uncommon Susceptibility loci: Pegasus is a genome-wide association nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 4,598 men of European ancestry diagnosed with prostate cancer from either arm of the trial and controls included 2,941 men of European ancestry without a diagnosis of cancer from the screening arm, matched on age and year of randomization. All subjects provided informed consent, and the study approved by the institutional review board at the National Cancer Institute. Funding:This work was supported by the GAME-ON U19 initiative for prostate cancer (ELLIPSE): U19 CA148537. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216, and U01-CA98758, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The ATBC study and PEGASUS was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. CAPS: The Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden was supported by the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant: K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant: 09-0677), the Hedlund Foundation, the Söderberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linnér’s Minne, Karlsson’s Fund for urological and surgical research. We thank and acknowledge all of the participants in the Stockholm-1 study. We thank Carin Cavalli-Björkman and Ami Rönnberg Karlsson for their dedicated work in the collection of data. Michael Broms is acknowledged for his skillful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. Hans Wallinder at Aleris Medilab and Sven Gustafsson at Karolinska University Laboratory are thanked for their good cooperation in providing historical laboratory results. UKGPCS would like to acknowledge the NCRN nurses and Consultants for their work in the UKGPCS study. We thank all the patients who took part in this study. This work was supported by Cancer Research UK (grants: C5047/A7357, C1287/A10118, C1287/A5260, C5047/A3354, C5047/A10692, C16913/A6135 and C16913/A6835). We would also like to thank the following for funding support: Prostate Research Campaign UK (now Prostate Cancer UK), The Institute of Cancer Research and The Everyman Campaign, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The MEC was supported by NIH grants CA63464, CA54281 and CA098758. 

Study phs001120

Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b Heart Health Study)

Participants from study sites that recruited during the original study funded by NICHD of pregnant people, called nuMoM2b, participated in this study. The nuMoM2b-HHS1 was a prospective observational follow-up study of the nuMoM2b cohort consisting of interval contacts via phone or web every 6 months to about a year, and an in-person visit 2 to 7 years after the end of the nuMoM2b pregnancy including: Demographics Self-administered questionnaires Clinical measurements Lab results An in-home sleep breathing assessment for the subset of participants with at least one valid sleep breathing assessment during nuMoM2b Abstraction of medical records for pregnancies subsequent to nuMoM2b involving self-reported adverse pregnancy outcomes or multiple births Abstraction of medical records of selected cardiovascular risk-related events or procedures reported by participants. The study capitalized on the rich and unique data prospectively collected during nuMoM2b (biomarkers, uterine artery Doppler studies, fetal growth, psychosocial determinants, sleep, and blood pressure) and rigorous definitions of adverse pregnancy outcomes. These data are stored in the NICHD repository DASH (https://dash.nichd.nih.gov/study/226675). A total of 8,838 nuMoM2b participants were targeted for contact during nuMoM2b-HHS and 7,872 participants were reached, of whom 7,003 completed one or more interval contacts. Of these, 5,206 agreed to the visit, and 4,508 attended an in-person visit.

Study phs002808

NHLBI TOPMed: Best ADd-on Therapy Giving Effective Response (BADGER)

BADGER is a 56-week randomized, double-blind, three-treatment, three-period cross-over trial that will evaluate the differential improvement in control that is achieved following three separate treatment interventions in children whose asthma is not acceptably controlled on a low dose of ICS (per NAEPP guidelines). All participants will enter an 8-week run-in period during which time they will receive a dose of 1x ICS (fluticasone 200 μg/day). During this 8-week time period, running 2-week averages to establish the lack of acceptable asthma control will be calculated. Thus, a child could qualify for randomization at any time during this 8-week run-in period. This approach should maximize both patient safety and successful enrollment. Children will continue to receive 1x ICS during the entire treatment phase. During each period of the treatment phase, they also will receive one add-on therapy in the form of LABA, LTRA or additional 1x ICS. The order of the add-on therapy assignment will be determined by randomization into one of six treatment sequences (order determined randomly). Each treatment period will be 16 weeks in length; the initial 4 weeks of each period will be considered to be the washout period for the previous treatment. The primary outcome measures will be frequency of asthma exacerbations, asthma control days, and FEV1.

Study phs001728

Whole genome sequencing of matched primary and metastatic acral melanomas

Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here we used whole genome sequencing to characterise somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair was more comparable to the rate reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumours, could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumour were propagated in the metastasis and one non-synonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

Study EGAS00001000169

Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

Study EGAS00001000055

Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

Study EGAS00001001179

1567 results for "Sweden+NDA+enforceability+one+party+signed"

in 14.74 milliseconds.