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• Amplicon sequencing of melanoma samples

  The types of biomarkers for skin tumors have been 1) biochemical markers in blood, urine, and body fluid, 2) histopathological markers, 3) genetic examination of tumor tissue, 4) tumor-susceptibility assessed by germ_x0002_line genetic examination. Biomarkers in a blood are frequently used in the treatment of cutaneous malignancies, but are not suitable for early detection of malignancies. Research on circulating tumor cells, cell free DNA, exosomes has been promoted in recent years, but clinical application is halfway. Based on these circumstances, the purpose of this study is to search for biomarkers for diagnosis, therapeutic effect, and follow-up of skin tumors, and to verify their usefulness.

  Study JGAS000351

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• Genome-wide DNA-methylation assessment by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison

  DNA-methylation is an important epigenetic feature in health and disease. Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). However, objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples obtained from 65 glioblastoma and 5 non-tumoral brain tissues, using a gold standard free Bayesian modeling procedure. While conditional specificity was adequate for both approaches, conditional sensitivity was systematically higher for HM450. Also the genome-wide characteristics were compared, revealing that the HM450 probes assess less than 10% of the regions identified as methylated by MethylCap-seq. Hence the latter method may detect more potentially relevant DNA-methylation, defined by either functional location or previously reported differentially methylated candidate regions. Our results therefore indicate that – at least for the tissue under study - both methodologies are complementary, with a higher sensitivity for HM450, but a far larger genome-wide coverage for MethylCap-seq. Note that here only the relevant MethylCap-seq data is deposited, for the HM450 data we refer to GEO (GSE60274).

  Study EGAS00001001191

• RNA-seq as a tool for evaluating human embryo competence

  The majority of embryos that are created through IVF do not implant. It seems plausible that rates of implantation would improve if we had a better understanding of molecular factors affecting embryo competence. Currently, the process of selecting an embryo for uterine transfer utilizes an ad-hoc combination of morphological criteria, the kinetics of development, and genetic testing for aneuploidy. However, no single criterion can ensure selection of a viable embryo. In contrast, RNA-sequencing of embryos could yield highly dimensional data, which may provide additional insight and illuminate the discrepancies among current selection criteria. Indeed, recent advances enabling the production of RNA-sequencing (RNA-seq) libraries from single cells have facilitated the application of this technique to the study of some transcriptional events in early human development. However, these studies have not assessed the quality of their constituent embryos relative to commonly used embryological criteria. Here, we perform proof-of-principle advancement to clinical selection procedures by generating high quality RNA-seq libraries from a trophectoderm biopsy as well as the remaining whole embryo. We combine state-of-the-art embryological methods with low-input RNA-seq to develop the first transcriptome-wide approach for use in future predictive embryology studies. Specifically, we demonstrate the capacity of RNA-seq as a promising tool in preimplantation screening by showing that biopsies of an embryo can capture valuable information content available in the whole embryo from which they are derived. Furthermore, we show that this technique can be used to generate a RNA-based digital karyotype, and to identify candidate competence-associated genes. Together, these data establish the foundation for a future RNA-based diagnostic in IVF.

  Dataset EGAD00001005044

• POISED (Peanut Oral Immunotherapy: Safety, Efficacy, and Discovery)

  Phase 2 POISED (Peanut Oral Immunotherapy: Safety, Efficacy, Discovery) Study In this randomized, double-blind, placebo-controlled (DBPC) clinical trial, blinded placebo group received oat flour, whereas in active participants, dosage was built-up for over ~ 52 weeks and subsequently maintained on 4000 mg peanut protein, daily for next 52 weeks. 80 (98.77%) per-protocol active participants passed the food challenge at week 104. Subsequently, for 12 weeks, peanut ingestion was avoided in a randomized group of 51 blinded active participants (i.e., peanut avoidance group). 21 (41.2%) participants in the peanut avoidance group passed the 4000 mg double-blind, placebo-controlled food challenge (DBPCFC) without any allergic reaction at week 117, thus demonstrating sustained unresponsiveness. These 21 participants continued oral immunotherapy (OIT) for every three months and afterwards were allowed to continue peanut OIT discontinuation if they passed. 8 participants passed the DBPCFCs, 12 months after peanut discontinuation (week 156), i.e. they achieved long-term sustained unresponsiveness with no allergic reaction in response to food challenge. For detailed description, please refer to Chinthrajah et al., PMID: 31522849.

  Study phs003071

• Immunodeficiency_

  We are doing single-cell RNAseq from B cells from monozygotic twins discordant for common variable immunodeficiency 1) 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002667

• Molecular_diagnosis_of_albinism

  Albinism is genetically heterogeneous rare genetic condition affecting 1:17000 in the Western world (but more frequent in Africa) whose main feature is a profound visual impairment, characterised by foveal hypoplasia, abnormal chiasmatic connections, nystagmus and photofobia. All these features result in severly altered visual acuity (<0,1), absent depth perception and poor night vision. People with albinism are primarily visually handicapped. In addition, for some types of albinism, the visual phenotype can be presented with partial or total hypopigmentation, hence resulting in a secondary phenotype which can lead to skin cancer if skin is not adequately protected. Recently a new syndrome has been described, FHONDA, with the same visual abnormalities of albinism but without pigment alteration. The traditional classification differentiates Oculoculatenous albinism (OCA), where hypopigmentation involves hair, skin and eyes versus Ocular Albinism (OA), where hypopigmentation only affects the eyes. These are non-sydrimic types of albinism. Some syndromic forms (Hermansky-Pudlak=HPS, Chediak-Higashi=CHS) affect cells beyond pigment cells, present in the lungs, immune system, platelets and intestines, resulting in more severe phenotypes that can be fatal. Mutations in at least 19 genes are assocaited with the corresponding types of albinism. Most hospitals will only diagnose the most frequent cases using traditional Sanger, MLPA approaches. Some will use CGH arrays. We aim to diagnose all cases of albinism through the Albinochip proposal, which combines a Sequenom first step of known mutations combined with subsequent NGS approaches. In some cases we fail to find a second mutation, these are good candidates for further full exome analyses. 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 EGAS00001002068

• Illumina HumanOmniExpress genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanOmniExpress BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotype calling algorithm used was Illuminus (Teo et al., 2007).

  Study EGAS00001000996

• Exome sequencing of UK Birth Cohorts - Born in Bradford

  Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights from population genetics to rare disease associations. Avon Longitudinal Study of Parents and Children (ALSPAC)recruited 14,775 babies of predominantly White ethnicity in the Avon county of south-west England between 1991 and 1992. Born in Bradford (BiB) is similarly focused on a particular local area, the city of Bradford in the north of England, and recruited 13,858 babies between 2007 and 2011, of whom ~41% self-report as white British and ~59% as other ethnicities, predominantly Pakistani. Millennium Cohort Study (MCS) is a national cohort that recruited 18,827 children born between 2000 and 2002, intentionally over-sampling areas with high child poverty, large ethnic minority populations, and smaller UK nations (Wales, Scotland and Northern Ireland) Available here is a subset of exome-sequenced parents and children from these studies (CRAMS and post-QC VCFs) as detailed in https://doi.org/10.12688/wellcomeopenres.22697 [doi.org]. Phenotypic data is also available by submitting an application to the corresponding cohort: https://borninbradford.nhs.uk/ [borninbradford.nhs.uk]

  Dataset EGAD00001015370

• Kids First: Genetic Basis of Fetal Alcohol Spectrum Disorders

  Fetal Alcohol Spectrum Disorder (FASD) is estimated to occur in at least 1-5% of all children in the USA and is a major public health issue. However, in addition to alcohol, other susceptibility factors, such as maternal or fetal genetic variation, must play a role as not all children prenatally exposed to alcohol are similarly affected. The proposed study will examine the role of genetic susceptibility for FASD. This work will help to inform more effective intervention efforts for this common congenital disorder.

  Study phs002594

• Genome-Wide associations of Lung Health Study (LHS)

  The 'Genome-Wide Associations Environmental Interactions in the Lung Health Study' at Johns Hopkins University aims to test for association between lung function decline as a primary outcome associated with chronic obstructive pulmonary disease (COPD) using banked DNA and phenotype data on 4,287 European Americans from the longitudinal, multicenter Lung Health Study (LHS). The broad goals of the LungGO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including COPD, in a subset of the LHS cohort. The Johns Hopkins University LHS cohort offers a unique opportunity to elucidate genetic variants that cause COPD. The Lung Health Study I was a randomized multicenter clinical trial with 5887 participants carried out from October 1986 to April 1994, designed to test the effectiveness of smoking cessation and bronchodilator administration in smokers aged 35 to 60 with mild lung function impairment. Participants were randomly assigned to one of three groups: usual care, who received no intervention smoking intervention with the inhaled bronchodilator ipratroprium bromide smoking intervention with an inhaled placebo. The effect of intervention was evaluated by the rate of decline of forced expiratory volume in one second (FEV1). For the GWAS, only the subset of European American LHS participants for whom lung function data from three time points or more are available. Thus, the GWAS represents 73% of the 5,887 volunteers who participated in the LHS study. Importantly, LHS subjects included had similar demographics (including age, gender and BMI) and rates of lung function decline (mean annual change in FEV1% predicted: -0.96 %/yr vs. -0.99 %/yr, p=0.57) compared with those not included in the GWAS, reflecting little selection bias for our primary outcome. They were, however, more likely to have quit smoking after 5 years. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to lung function through large-scale genome-wide association studies of smokers enrolled in a multicenter clinical trial. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000335

• Submitters and requesters Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue Here, we show the amount and global distribution of submitters and requesters Requester accounts created by country The below figure represents the number of requester accounts by country. In most of the cases cases, country was inferred from the requester email domain. Those requesters whose email domain could not be assigned to a country such as @gmail.com, are not included. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('requester-country', 'https://stats.ega-archive.org/requester/country') pieChart('requester-country-pie-chart', 'https://stats.ega-archive.org/requester/country','Requester accounts created by country') Requester accounts created by year The below figure represents the number of requester accounts by year. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('requester-year', 'https://stats.ega-archive.org/requester/year', ['Requester Accounts', 'Years'], true) Industry requester accounts The below figure represents the top 15 industry requesting companies. Industry Requester Accounts Download as PNG Download as JPG Download as WEBP Download as CSV pieChart('industry-requester-accounts', 'https://stats.ega-archive.org/industry/requester/accounts', 'Industry Requester Accounts') Submitter accounts created by country The below figure represents the number of submitter accounts by country. Location was infered from the requester email domain. Submitter Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('submitter-accounts', 'https://stats.ega-archive.org/submitter/accounts/country') pieChart('submitter-accounts-pie-chart', 'https://stats.ega-archive.org/submitter/accounts/country','Submitter accounts created by country') Submitter accounts created by year The below figure represents the number of submitter accounts by year. Submitter Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('submitter-users-year', 'https://stats.ega-archive.org/submitter/users/year', ['Submitter Accounts', 'Years'], true) DAC Members by Country The below figure represents the number of DAC members by country. DAC Members by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('dac-members-by-country', 'https://stats.ega-archive.org/dac_member/country') pieChart('dac-members-by-country-pie-chart', 'https://stats.ega-archive.org/dac_member/country','DAC members by country')

  Documentation about/statistics/community

• The malaria-protective human glycophorin structural variant DUP4 shows somatic mosaicism and association with hemoglobin levels

  Glycophorin A and glycophorin B are red blood cell surface proteins that are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A - glycophorin B fusion gene, and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40% Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant, and reveal somatic variation in copy number of the glycophorin A- glycophorin B fusion gene. By developing a simple, specific, PCR-based assay for DUP4 we show the DUP4 variant reaches a frequency of 13% in a malaria-endemic village in south-eastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation, and show that it is associated with a malarial-related phenotype in a non-hospitalizedlongitudinally-followed population.

  Study EGAS00001003239

• Reliable assessment of telomere maintenance mechanisms in neuroblastoma

  Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

  Study EGAS00001006510

• Genome-Wide Association Study of Genetic Susceptibility for Graft-vs-Host Disease Cohort 1

  Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, gastrointestinal (GI) tract, and liver in recipient. More than half of all Allo-HSCT recipients develop different degrees of GVHD (grades I-IV). About 20% of recipients develop severe GVHD (grades III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in human leukocyte antigen (HLA) haplotypes that are routinely checked for donor selection. Even when donors and recipients are HLA-identical, many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent Allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP and Medical College of Wisconsin. In the second aim, we will validate the association between high risk genotypes detected in the first aim and severe GVHD in 1,750 donors and 1,750 recipients of Allo-HSCT, and perform the joint analysis with the discovery samples. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an ex vivo surrogate for an alloimmune response.

  Study phs002185

• 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

• Geriatric Oncology Database of genotypes and methylation, gene expression, clinical data, and survey results on psychosocial and physical conditions in Japanese elderly cancer patients to establish truly effective treatment strategy

  Owing to the advent of super-aged society, cancer mortality in Japan is forecasted to become an all-time high. The management of elderly patients with cancer is a serious health issue and the need for specific care guidelines for this population is critical in Japan. The significant individual differences in comorbidity, physical and mental functioning, and social problems among aging individuals are obstacles to the progress. The response to cancer treatment varies significantly among patients, even in the same stage of the same type of cancer. Older aged patients are still less likely to be offered participation in clinical trials, thus the number of clinical evidences is limited. The molecular mechanisms regulating the physiological process of ageing and senescence, and cancer are far from understood. To establish a truly effective treatment algorithm, we attempted to develop a geriatric oncology database for genotypes and methylation, gene expression, clinical data, and survey results on psychosocial and physical conditions in Japanese elderly cancer patients in this retrospective study. The genomic analysis was performed in 62, 106, and 173 cases, respectively for gastric, colon and lung cancers. The clinical data and survey results on psychosocial and physical conditions were collected from 166, 313, and 344 patients respectively for gastric, colon and lung cancers, and also collected from 357, 49, and 300 benign cases respectively for cardiovascular disorder, respiratory dysfunction, diabetes and nephropathy as the analysis control.

  Study JGAS000061

• Genome-wide NanoRCS of cfDNA from plasma of healthy individuals

  Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We adapted a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy controls.

  Study EGAS50000000695

• Neuroblastoma Genome-Wide Association Study (NBL-GWAS)

  Neuroblastoma is a malignancy of the developing sympathetic nervous system that most commonly affects young children and is often lethal. The etiology of this embryonal cancer is not known. We have performed a whole genome scan for association of neuroblastoma with SNP genotypes and copy number variation to discover predisposition loci. We therefore initiated a genome-wide association study (GWAS) in 2007 focused on neuroblastoma patients identified through the Children's Oncology Group (COG; 238 member institutions). Control patients for this study are children cared for at the Children's Hospital of Philadelphia (CHOP) without a diagnosis of cancer. The study was designed to collect up to 5000 neuroblastoma cases and 10,000 controls and is powered to detect common susceptibility variants in Caucasian and African American patients. Whole genome genotyping is being performed on the Illumina HH550 SNP array.

  Study phs000124

• Kidney_transplant_nephrectomy_scRNAseq

  Single cell transcriptomics study of tissue from human kidney transplant nephrectomies Tissue is acquired from kidney transplant nephrectomies, homogenised and disaggregated to a single cell suspension prior to droplet encapsulation single cell RNAseq (10X protocol) or plate based single cell RNAseq (SS2 protocol). Human tissues, including the kidney are seeded with a tissue resident immune cell network throughout life. These cells may self renew in situ or be replaced by circulating precursors which enter the tissue in response to tissue specific niche and inflammatory signals. We are using single cell RNA sequencing of kidney transplant nephrectomy tissue to 1) understand the immune cell populations which are resident within the human kidney 2) identify which of these populations is donor or recipient derived. 3) Uncover the temporal dynamics of donor/recipient chimerism in the the human kidney following transplantation. 4) Understand transcriptional differences between organs removed for a variety of reasons (infection, chronic rejection, vascular emergencies) 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 EGAS00001003935

• “Castration-persistence” is a distinct state of tolerance to androgen receptor targeting therapies in prostate cancer

  Androgen receptor (AR) signalling is important in prostate cancer progression, and therapies that specifically target this pathway are the mainstay of treatment for advanced disease. Treatment however is non-curative, and resistance develops inevitably with time. Although the mechanisms that drive progressive ‘castration resistant’ disease are reasonably well characterized, how tumours survive acute pathway inhibition is unclear. We performed a neo-adjuvant study of a novel combination of AR targeting therapies, and noted that the objective response to treatment was highly variable. To determine what was driving tumour persistence in poorly responding patients, we comprehensively characterised pre- and post-treatment samples were using both whole genome and RNA-sequencing. We find that ‘castration-persistence’ is a distinct state from ‘castration-resistance’, and is mediated by global transcriptional reprogramming leading to transitional EMT state, which is shared with benign luminal epithelial cells. This appears to be AP-1 and KLF driven, and represents and integration of multiple signalling pathways, particularly IGF2, offering a number of tractable strategies to improve clinical response to AR targeting therapies.

  Study EGAS00001003172

• Sequencing Study in COPD cases and controls

  Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n=8), as well as from ex-smokers with variable degrees of COPD (n=4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data.

  Study EGAS00001003406

• Ataxia Gene Identification by Integrated Genomic Analysis

  Ataxias are a group of diseases that result in a lack of coordinated muscle movement. Hereditary ataxias are genetically heterogeneous and it is reported that 40% of suspected genetic ataxias currently have an unknown cause. We used exome sequencing to detect mutations responsible for ataxia. We sequenced, when available, multiple individuals per family to identify family specific mutations and further confirmed segregation of variants using samples from available affected and unaffected family members.

  Study phs000757

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• Novel Epigenetic Markers for Toxicity after Intraoperative and Conventional Radiotherapy for Breast Cancer

  Ionizing radiation is a common treatment option for cancer but its use is limited by the unpredictable and highly heterogeneous onset of late side effects, especially radiation-induced fibrosis. Clinically applicable biomarkers and effective treatments for radiation fibrosis are currently unavailable. In order to identify novel markers we ran a genome-wide DNA methylation screen in primary dermal fibroblasts obtained from breast cancer patients before intraoperative radiotherapy. Cells from patients developing fibrosis within a three-year follow up were compared to those without fibrosis (12 individuals per group). Illumina Infinium HumanMethylation450 BeadChip Technology was used.

  Study EGAS00001001279