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• Assessing mitochondrial bioenergetics in coronary artery disease: A translational left ventricular tissue study in humans (The AMBITION study).

  Severe or recurrent myocardial ischemia can lead to long-term left ventricular (LV) dysfunction and heart failure in patients with coronary artery disease (CAD). In this study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients with evidence of preoperative inducible ischemia undergoing coronary artery bypass grafting (CABG). During surgery, paired transmural LV biopsies were acquired on the beating heart from a region of inducible ischemia (determined by stress perfusion cardiovascular magnetic resonance), and a remote LV segment. From 33 patients, 63 LV biopsies were acquired on the beating heart during CABG, comparing to analysis of LV samples from 11 donor hearts. The global myocardial ATP/ADP ratio was reduced in CAD patients as compared to donor LV tissue with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained during CABG from LV segments with or without inducible ischemia revealed no significant difference in the ATP/ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Finally, differential metabolite analysis suggested dysregulation of several intermediates in patients with impaired LVEF; this notably included the tricyclic acid cycle metabolite, succinate. Overall, our results suggest that viable human myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

  Study EGAS00001007351

• Immunogenomic analysis of tumor infiltrating B cells in gastric cancer

  Despite the accumulating evidences of the significance of humoral cancer immunity, its molecular mechanisms have largely remained elusive. This study aimed at profiling the global picture of the humoral cancer immunity in view of immune repertoire characteristics of tumor-infiltrating B cells. In this study, we investigated B-cell repertoire (BCR) / immunoglobulin (Ig) sequencing of tumor infiltrating B cells in 102 clinical gastric cancers. First, total RNAs were extracted from frozen gastric cancer tissues and corresponding normal gastric mucosa; then, BCR/Ig repertoires of tumor-infiltrating B cells were amplified by target PCR using multiplex primer sets available from iRepertoire(R), inc. Subsequent next-generation sequencing data obtained by the Illumina platform were aligned onto human BCR/Ig repertoire sequence. This dataset contains the repertoire sequencing data of 102 gastric cancer cases analyzed in this study.

  Study JGAS000242

• TP53 variant detection analysis in high grade serous epithelial ovarian cancer

  The aim of this study was to detect in the DNA purified from PAP test samples collected years before the diagnosis of high grade serous epithelial ovarian cancer the presence of the clonal pathogenic TP53 variant identified in the matched primary tumor biopsy. In this specific part of the study, we analyzed FFPE tumor samples to identify clonal pathogenic variants to be tested in matched PAP tests.

  Study EGAS00001004361

• BarcUVa-Seq (Biology of Colorectal Cancer Risk Enhancers)

  This study was designed to generate a cohort of normal colon mucosal biopsies from the "average risk" population. Its primary aims included the development of an RNA-seq dataset of normal colon mucosal biopsies across three colon regions (ascending, transverse and descending). Further, we aimed to provide plausible prioritization to genetic components of colorectal cancer risk by employing methods such as expression quantitative trait loci analysis. In doing so, we provide a novel reference dataset for the study of colon cancer risk in the healthy colon epithelium. RNA-seq was performed in batches on an Illumina HiSeq 2500 (batch 1-7) or NovaSeq 6000 (batch 8) on a total of 463 samples. Matched genotyping data was generated on the Illumina OncoArray BeadChip. Phasing was carried out using Minimac 3 and imputation was performed using The Haplotype Reference Consortium panel on the Michigan Imputation Server.Genotype and RNA-seq data will be made available in dbGaP.

  Study phs003338

• Divergence between high metastatic tumor burden and low circulating tumor DNA concentration in metastasized breast cancer

  Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.

  Study EGAS00001000625

• Epigenetic Changes in Immune Response and Oncogenesis Related Genes Caused by Heavy Metal Long-Term Exposure

  Our study investigated methylation changes in CpG islands located in immune response and oncogenesis related genes in humans induced by long-term environmental heavy metal exposure. We assessed the methylation levels of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5 and IGF2/H19 genes by targeted bisulfite sequencing (target enrichment by 48.48 Access Array Integrated Fluidic Circuit (Fluidigm, USA) in a cohort of 40 subjects living near a metal mining area (the Kapan mining region, Armenia) and 40 unexposed subjects. We performed linear regression on our data to find differentially methylated positions with adjustment for gender, age, BMI class, smoking, and plasma concentrations of 21 essential and non-essential metals detected by ICP-MS. Our study showed hypomethylation of five CpG sites in the NFKB1 promoter region in the exposed group. According to our findings, the methylation changes of CpG sites in NFKB1, CDKN2A, IGF2 and ESR1 genes are associated with multiple and specific metal exposures. Targeted bisulfite sequencing data obtained for 80 subjects who participated in this study are available through dbGaP. The tables contain information about age, sex, BMI, smoking and exposure status, as well as race and ethnicity of the study participants.

  Study phs003392

• Papuan Y chromosome Diversity Panel

  Island Southeast Asia and Oceania host one of the world’s richest assemblages of human phenotypic, linguistic and cultural diversity. Despite this, the region’s male genetic lineages are globally among the last to remain unresolved. We compiled ~9.7 Mb of Y chromosome sequence from a diverse sample of over 380 men from this region, including 152 first reported here. The granularity of this dataset allows us to fully resolve and date the regional Y chromosome phylogeny. This new high-resolution tree confirms two main population bursts: multiple rapid diversifications following the region’s initial settlement ~50 kya, and extensive expansions <6 kya. Notably, ~40-25 kya the deep rooting local lineages of C-M130, M-P256, and S-B254 show almost no further branching events in Island Southeast Asia, New Guinea and Australia, matching a similar pause in diversification seen in maternal mitochondrial DNA lineages. The main local lineages start diversifying ~25 kya, at the time of the Last Glacial Maximum. This improved Y chromosome topology highlights localized events with important historical implications, including pre-Holocene contact between Mainland and Island Southeast Asia, potential interactions between Australia and the Papuan world, and a sustained period of diversification following the flooding of the ancient Sunda and Sahul continents as the insular landscape observed today formed. The high-resolution phylogeny of the Y chromosome presented here thus enables a detailed exploration of

  Study EGAS00001006025

• Determining genome-wide binding of ETS2 by CUT&RUN in primary human macrophages

  This dataset consists of sequencing data from an ETS2 CUT&RUN experiment in primary inflammatory (TPP) macrophages (n = 2). Pre-cultured TPP macrophages were harvested and processed immediately using the CUT&RUN Assay kit (Cell Signaling) according to the manufacturer’s instructions with the following modifications (essentially, avoiding the use of ConA-coated beads). Anti-ETS2 (ThermoFisher) or IgG control (Cell Signaling) antibodies were used for targeted digestion of chromatin. For each donor, 5x10^5 cells were pelleted, washed in Wash Buffer, and resuspended in Antibody Binding buffer. Cells were incubated with antibodies (1:100 dilution for anti-ETS2) for 2h at 4°C. After washing in Digitonin Buffer, cells were incubated with pA/G-MNase for 1h at 4°C. Cells were washed twice in Digitonin Buffer, resuspended in the same buffer and cooled for 5 minutes on ice. Calcium chloride was added to activate pA/G-MNase digestion and cells were incubated for 30 minutes at 4°C before Stop Buffer was added, and cells were incubated for 10 min at 37°C to release cleaved chromatin fragments. Supernatants were collected by centrifugation and DNA extracted using DNA Purification Buffers and Spin Columns (Cell Signaling). Library preparation was performed according to a protocols.IO protocol (dx.doi.org/10.17504/protocols.io.bagaibse) using the NEBNext Ultra II DNA Library Prep Kit. Size selection was performed using AMPure XP beads (Beckman Coulter) and fragment sizes were determined using an Agilent 2100 Bioanalyzer (High Sensitivity DNA kit). Equimolar pools of indexed libraries were sequenced on an Illumina NovaSeq 6000 (100bp PE reads). Raw data are provided as 100 bp paired-end Illumina reads.

  Dataset EGAD00001011349

• Peruvian Genome Project - Whole Genome Sequencing

  In this study, we sequence 150 genomes to high coverage from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date.

  Study EGAS00001004995

• Expanding CIRdb, a comprehensive catalog of whole-exome sequencing data of Canary Islanders

  This study aimed to comprehensively characterize the full spectrum of small genetic variation among 920 unrelated donors from this population based on whole-exome sequencing data to further develop CIRdb as the Canary Islanders-specific reference catalog of genetic variation.

  Study EGAS50000001726

• Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia (H021)

  Here we report the case of an acute promyelocytic leukemia (APL) patient who, though negative for FLT3 mutations at diagnosis, developed isolated FLT3-TKD positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-year old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA protocol. 13 months after start of ATRA maintenance the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA in the bone marrow. Following treatment with arsenic trioxide (ATO) and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for two years after completion of therapy. Whole exome sequencing and subsequent ultradeep targeted re-sequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads (51%)), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.H021

  Study EGAS00001001848

• OCCAMS_Oesophageal_Cancer_Organoids_1

  ***THIS DATA CAN ONLY BE USED FOR NON-COMMERCIAL CANCER RESEARCH*** Sequencing of organoid cell lines derived from oesophageal tumour sections taken from patients diagnosed with primary oesophageal cancer who underwent tumour resection surgery.

  Study EGAS00001001382

• Complex genotype-phenotype relationships shape the response to treatment of Down Syndrome Childhood Acute Lymphoblastic Leukaemia

  Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.

  Study EGAS50000001287

• RNAseq_of_ribosomal_footprints

  Cancer genes can affect ribosomal RNA processing and this can underlie their essentiality to cells, making them cell-essential in the same way as ribosomal genes themselves. We want to confirm this, in order to understand the results of our CRISPR drop-out screens.NOTE FROM BESPOKE TEAM: Run a single read 1 (forward read) of 30 bases, then an index 1 read as normal. This would fit a 50cycle kit

  Study EGAS00001001591

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

  Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

  Study EGAS00001002609

• Prognostic relevance of microenvironmental factors CD163 and CD8 combined with EZH2 and chromosome 18 gain in a validation cohort of follicular lymphoma patients of the Lunenburg Lymphoma Biomarker Consortium

  Background: In follicular lymphoma (FL), studies addressing the prognostic value of microenvironment-related immunohistochemical (IHC) markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium (LLBC) performed a validation study for published markers. Methods: To maximize sensitivity, an end-of-spectrum design was applied for 122 uniformly immunochemotherapy-treated FL patients retrieved from international trials and registries; early failure (EF): progression or lymphoma-related death <2 years versus long remission: response duration of >5 years. IHC staining for T-cells and macrophages was performed on tissue microarrays from initial biopsy and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. Results: 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (p=0.006), gain of chromosome 18 (p=0.002), low percentages of CD8+ cells (p=0.011) and CD163+ areas (p=0.038) were associated with EF. No significant differences in other markers were observed, thereby refuting previous claims on their prognostic significance. Conclusion: Using an optimized study design, this LLBC study validates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of EF to immunochemotherapy in FL.

  Study EGAS00001002049

• MethylScan data of plasma samples

  10ng from each cfDNA sample was used as the input material. For gDNA samples, 1.5-2ug each was first sonicated by Covaris R230 system (Woburn, MA). Next, size-selection with 0.8x-1.5x two-step Ampure XP beads was performed to enrich the 150-200bp fragments. 200ng of the size-selected gDNA was used as input material. The pre-capture library construction was performed with NEB UltraII DNA library prep kit for Illumina (Ipswich, MA) and the adapter was the methylated EM-seq adapter. Before the first PCR amplification, the gDNA samples were subjected to bisulfite conversion by QIAGEN Epitect kit, and cfDNA samples were subjected to enzymatic conversion by NEBNext enzymatic methyl-seq kit if the hybrid capture panel designed for converted DNA was used downstream. Twist panel hybrid capture was performed with their standard protocol (Twist Bioscience, South San Francisco, CA). The concentration of the post-capture library after the second PCR amplification was measured by Qubit 1xdsDNA HS kit (ThermoFisher, Waltham, MA). Their quality was examined by TBE-UREA PAGE and Bioanalyzer before sequencing. Libraries were then sequenced with 150bp paired-end reads on Illumina machines by Genewiz, Inc. (South Plainfield, NJ, USA). This dataset contains MethylScan data of the plasma samples from 248 noncancer individuals and 27 cancer patients (17 liver and 10 GI-tract cancers).

  Dataset EGAD00001015815

• 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

• Sensitive and robust liquid biopsy-based detection of PIK3CA mutations

  Over the last years, the treatment of hormone receptor-positive metastatic breast cancer patients has dramatically changed. Combination strategies attempting to overcome resistance to endocrine therapy such as targeting the PI3 kinase pathway are gaining importance. The phase III SOLAR-1 trial demonstrated the benefit of the addition of alpelisib to fulvestrant, thereby providing further clinical evidence of the increasing importance of PIK3CA testing. Here, we performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations in HR-positive metastatic breast cancer patients. Plasma samples and the latest available tumor tissue from 69 patients with metastatic hormone-receptor positive breast cancer were analyzed for PIK3CA hotspot mutations. A high-resolution NGS assay (SiMSen-Seq) was used for plasma samples covering 11 recurrent PIK3CA mutations, used for stratification in SOLAR-1. Additionally, mFAST-SeqS was used to estimate the tumor fractions in the plasma samples. For tumor tissue samples, targeted Ion Torrent NGS was employed. Matched tissue and plasma samples were available from 63 patients. PIK3CA mutations were detected in 46.1% of the tissue samples and in 50.7% of the plasma samples. The variant allele frequency (VAF) ranged from 4.36% to 72.93% with a median of 28.60% in tissue samples, and from 0.28% to 49.85% with a median of 1.17% in plasma samples. The most frequent variants in tissue and plasma were H1047R, E545K, and E542K. We detected at least one of 11 PIK3CA mutations from the SOLAR-1 trial in 51/63 patients, both in tissue and plasma. In 7 patients, such mutations were found only in plasma. In 5 patients, PIK3CA mutations found in tissue were not detectable in ctDNA, 2 of which had a low tumor fraction.Together, in 33/67 plasma samples without detectable PIK3CA mutations, 18 samples had elevated tumor fraction, implicating true negative results. In the remaining 15 patients with low tumor fraction, additional tissue analysis was needed. SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted, mutation-independent approach for detecting ctDNA fractions may confirm a negative PIK3CA result and thereby enhance the performance of the SiMSen-Seq test. This combinatory approach for selecting suitable patients for alpelisib treatment should be validated in larger patient cohorts.

  Study EGAS00001004940

• UK10K_RARE_THYROID

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.Two cohorts of subjects are being analysed: Individuals with Congenital Hypothyroidism (CH) due either to dysgenesis or dyshormonogenesis; Patients with Resistance to Thyroid hormone (RTH), a disorder characterized by elevated thyroid hormones and variable tissue refractoriness to hormone action. The CH cohort has been enriched for genetic aetiologies by recruiting cases that are familial, on a consanguineous background or syndromic. The RTH cohort consists of cases in which candidate gene analyses have been negative.For further information with regard to this cohort please contact Krishna Chatterjee (kkc1@medschl.cam.ac.uk).

  Study EGAS00001000131

• Donor InSight III study: Participants typed during UK Biobank version 2 array development phase

  The Donor InSight III study, undertaken by Sanquin research, recruited 3,046 Dutch blood donors between 2015 and 2016. The purpose of the study was to gain more insight into characteristics of donors, their motivations and health. All participants were at the time of recruitment active blood donors. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Dataset EGAD00001005026

• Tagged-amplicon deep sequencing

  This dataset contains a collection of tumour samples from high grade serous ovarian carcinoma patients with recurrent disease collected near the point of diagnosis as well as tumour samples collected after patient relapse upon or some time after study entry. Whole blood samples were also collected from patients at study entry for the purpose of germline variant detection. The majority of diagnosis samples were preserved in neutral buffered formalin whereas the majority of post-relapse samples were preserved in universal molecular fixative (UMFIX, Sakura Finetek USA, Inc). DNA was extracted and the tagged-amplicon deep sequencing assay was applied (TAm-Seq, Forshew et al. 2002, Sci Transl Med) with the aid of fluidigm access array technology. Targeted loci were sequenced at very high depths (typically >100X) for the detection of both somatic and germline variants. Sequenced reads were aligned to the GRCh37 reference genome (release hs37d5).

  Dataset EGAD00001011058

• Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells

  Most human breast cancers have already diversified genomically when they first become clinically evident, by which time extensive heterogeneous histopathologies, transcriptomes and growth patterns are also apparent. Accordingly, important initial events and the cellular context in which they occur have been difficult to characterize. Using DNA barcoding, we now demonstrate the high efficiency with which both purified basal and luminal cells isolated directly from normal adult human mammary tissue can be rapidly transformed by a single oncogene (KRASG12D) resulting in the production within 8 weeks in vivo of serially transplantable, polyclonal, invasive ductal carcinomas that are phenotypically heterogeneous and transcriptionally distinct from the initial cells transduced. Barcoding also revealed a consistent dramatic change in the clonal content of passaged tumours. This system thus provides a powerful new platform for examining early events in the genesis, evolution and treatment response of malignant human mammary cells generated using defined mutations.

  Study EGAS00001001310

• POT1 splice site mutant analysis

  We are interested in the contribution mutations in the Shelterin complex protein POT1 may have to the development of melanoma. We have identified a patient who carries a splice site mutation in POT1 and as part of our analysis of this gene we aim to sequence the transcriptome of this patient to see how this mutation influences splicing. RNA has been obtained from lymphocytes collected from the patient.

  Dataset EGAD00001000786

• Targeted sequencing of healthy individuals, aged individuals and AML patients

  Targeted sequencing using BD Rhapsody with 462 mRNA and 97 antibodies of healthy young and aged adult as well as AML bone marrow mononuclear cells from iliac crest aspirations. Please note raw and integrated gene expression data, cell type annotation, metadata and dimensionality reduction are available as Seurat v3 objects through figshare. Access link is https://figshare.com/s/0fda29b169c719223ee3.

  Dataset EGAD00001008188

• Single Cell Analysis of Human Airways in Healthy and Asthma volunteers

  Bronchoscopies were collected from healthy and asthma volunteers. Cohort inclusion criteria for all subjects were: age between 40 – 65 years and history of smoking < 10 pack years. For the asthmatics, inclusion criteria were: age of onset of asthmatic symptoms ≤12 years, documented history of asthma, use of inhaled corticosteroids with(out) β2-agonists due to respiratory symptoms and a positive provocation test (i.e. PC20 methacholine ≤8mg/ml with 2-minute protocol). For the non-asthmatic controls, the following criteria were essential for inclusion: absent history of asthma, no use of asthma-related medication, a negative provocation test (i.e. PC20 methacholine >8 mg/ml and adenosine 5'-monophosphate >320 mg/ml with 2-minute protocol), no pulmonary obstruction (i.e. FEV1/FVC ≥70%) and absence of lung function impairment (i.e. FEV1 ≥80% predicted). Asthmatics stopped inhaled corticosteroid use 6 weeks prior to all tests. All subjects were clinically characterised with pulmonary function and provocation tests, blood samples were drawn, and finally subjects underwent a bronchoscopy under sedation. If a subject developed upper respiratory symptoms, bronchoscopy was postponed for ≥6 weeks. Fibreoptic bronchoscopy was performed using a standardised protocol during conscious sedation. Six macroscopically adequate endobronchial biopsies were collected for this study, located between the 3rd and 6th generation of the right lower and middle lobe. Extracted biopsies were processed directly thereafter, with a maximum of one hour delay. The medical ethics committee of the Groningen University Medical Center Groningen approved the study, and all subjects gave their written informed consent.

  Dataset EGAD00001005064

• The Genetic History of Greenlandic-European contact

  The Inuit ancestors of the Greenlandic people arrived in Greenland close to 1000 years ago. Since then, Europeans from many different countries have been present in Greenland. Consequently, the present-day Greenlandic population has ~25% of its genetic ancestry from Europe. In this study, we investigated to what extent different European countries have contributed to this genetic ancestry.

  Study EGAS00001004933

• Whole genome sequencing of EBV Associated Nasopharyngeal Carcinoma

  Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.

  Study EGAS00001004705

• early-stage ESCC sequencing study

  We performed a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 esophageal squamous cell carcinoma phase (ESCC) patients, covering 9 histopathological stages in 3 phases as nontumor phase (NT phase), intraepithelial neoplasia phase (IEN phase), and ESCC phase. Proteogenomics elucidated the stage-specific molecular characterization and defined the cancer-driving waves along with the mutation accumulation in EC progression. The integrated multi-omics uncovered the chromosome 3q gain was the key event in the transmit from the NT to IEN phase, disclosed the top mutation of TP53 enhanced cell cycle and DNA replication in the IEN phase, and revealed the ESCC phase mutations of AKAP9 and MCAF1 elevated glycolysis and Wnt signaling, respectively. Furthermore, the trajectory analysis identified 6 major tracks related to different clinical features during ESCC progression. Growingly enhanced and hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) was detected and considered as a drug target in ESCC progression. Collectively, this study provides insight into the understanding of ESCC molecular mechanism and a valuable resource for the development of therapeutic targets.

  Study EGAS00001006126

• Targeted DNA sequencing and mRNA sequencing data from patients with peritoneal metastasis from colorectal cancer

  Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors.

  Dataset EGAD50000000593

• Oxford Nanopore long-read sequencing data of high-grade serous ovarian cancer

  This dataset comprises whole-genome Oxford Nanopore long-read sequencing data from six high-grade serous ovarian cancer (HGSOC) patients, including cryopreserved, pre-treatment tumor tissues and matched peripheral blood samples (12 samples in total). High-molecular-weight DNA was prepared using the SQK-LSK114 Ligation Sequencing Kit and sequenced on FLO-PRO114M flow cells (R10.4.1). Basecalling was conducted using the super-accurate (SUP) model, enabling simultaneous detection of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). The dataset includes BAM files containing base modification information for downstream genomic and epigenomic analyses.

  Dataset EGAD50000001509

• RIP-SeqRaw data

  This dataset contains the raw count matrix generated in the PTBP1 project. Sequencing data were obtained from bulk directional RNA-seq and RIP-seq experiments performed on a NovaSeq 6000 platform (2×100 bp paired-end reads). Read counts were computed using HTSeq-count, without normalization. The dataset comprises two groups of samples: controls and patients. For each group, both input and immunoprecipitated samples are available. Patient samples correspond to skin biopsies from individuals affected by a neurodevelopmental disorder associated with variable skeletal dysplasia and disproportionate short-limbed short stature.

  Dataset EGAD50000001722

• small RNA-sequencing and RNA-sequencing of human brain tissue with temporal lobe epilepsy

  This data set contains the raw .fastq files from two RNA-sequencing experiments and two small RNA-sequencing experiments. Both control brain tissue and tissue from sufferers of mesial temporal lobe epilepsy were sequenced. Two different brain regions were sequenced; the cortex and the hippocampus. For more details please see: Mills, James D., et al. "Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs." Neurobiology of disease 134 (2020): 104612.

  Dataset EGAD00001005735

• UK10K NEURO ASD MGAS

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The MGAS (Molecular Genetics of Autism Study) samples are from a clinical sample seen by specialists at the Maudsley hospital and who have had detailed phenotypic assessments with ADI-R and ADOS.For further information on this cohort please contact Patrick Bolton (patrick.bolton@kcl.ac.uk).

  Study EGAS00001000113

• Dataset of the transcriptomic profiling of skin biopsies from 221 psoriasis patients following treatment with Zasocitinib

  This dataset contains the paired fastq files generated from 221 samples collected from patients with moderate-to-severe plaque psoriasis and sequenced on the Illumina NovaSeq 6000 platform. Patients were randomized in a 1:1:1:1:1 ratio to receive oral Zasocitinib at doses of 2 mg, 5 mg, 15 mg, 30 mg, or placebo once daily for 12 weeks. Clinical response was defined as achieving a PASI 75 response at week 12, while histologic response was defined as the absence of KRT16-positive cells in lesional skin after 12 weeks of treatment.

  Dataset EGAD50000002224

• Whole genome sequencing data for Molecular Characterization of ETMRs

  This dataset contains whole genome sequencing data from 59 samples. WGS libraries were prepared using the Illumina TruSeq Nano DNA LT Library Prep or TruSeq Nano DNA HT Library Prep Kit following the manufacturer’s instructions. In brief, 100 ng of genomic DNA was fragmented to approximately 350 bp using a Covaris ultrasonicator (Covaris). The fragmented DNA was then end-repaired, size-selected using magnetic beads, extended with an ‘A’ base on the 3′ end and ligated with TruSeq paired-end indexing adapters. Up to four lanes per sample have been sequenced resulting in 222 Fastq files (paired end).

  Dataset EGAD00001006211

• Embryonic tumour transmission in monozygotic twins

  We have a case of two siblings (twins) who were born with nodular blue rashes over their body. The first twin had a large periorbital subcutaneous mass which was diagnosed as infantile undifferentiated sarcoma. This baby was too systematically unwell for chemotherapy and died at 12 days of age. The second sibling received two cycles of emergency chemotherapy however died due to disease progression and secondary haemorrhage at 2 months of age. Post-mortem normal and tumour samples have been taken. In addition to placental tissue and parental germline DNA, the goal will be to investigate intra-uterine transfer of sarcoma and the phylogenetic relationship of tumours in both twins.

  Dataset EGAD00001015681

• microRNA sequencing data from pediatric obesity lifestyle intervention study

  This dataset contains small RNA sequencing data generated from peripheral blood samples collected from children and adolescents with obesity enrolled in a 12-month multicenter lifestyle intervention study. Libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq platform using single-end 75 bp sequencing. The dataset includes fastq files and associated metadata for the identification of circulating microRNA biomarkers associated with response to lifestyle modification and obesity-related metabolic traits.

  Dataset EGAD50000002758

• Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

  Current methods available for pre-implantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo. Detection of these types of mutations requires whole genome sequencing (WGS). In this study advanced massively parallel WGS was performed on three 5-10 cell biopsies from two blastocyst-stage embryos. Overall, greater than 95% of each genome was called and experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false positive rate of ~1 error per Gb. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease causing mutations and reduce the incidence of genetic diseases.

  Study phs000858

• Sequencing Lymphoma

  This repository contains sequencing data to describe the genomic profiles of several B-cell lymphomas including follicular lymphoma and Hodgkin lymphoma. We have used several different high throughput sequencing technologies to interrogate genomic DNA and RNA from tumor cells obtained from lymph node biopsies and normal cells obtained from skin biopsies and peripheral blood mononuclear cells. A number of sequencing platforms for DNA, RNA, and protein were used to generate the data. These platforms include exome sequencing and a custom capture panel (NimbleGen) that targets 7.05 MB corresponding to the exons and splice sites of 1716 genes related to lymphoma biology (WUSM-LP). Other platforms include single-cell RNA-seq and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), which was used to describe transcriptional and proteomic changes in immune cell subsets within lymphoma patients pre- and post-therapy.

  Study phs001229

• Cancer of Low survival and UnMet Need – Pathologist Initiated

  Despite significant advances in diagnostic cancer histopathology, a subset of tumors remain unable to be classified using WHO criteria. The resulting diagnostic uncertainty can result in inappropriate clinical management and negative patient outcomes. We investigated whether combining histopathology with whole genome and transcriptome sequencing (WGTS) could improve the classification of tumors that posed diagnostic dilemmas despite extensive histopathology and standard molecular work-up at a quaternary oncology center. We successfully sequenced 45 tumors from an initial set of 54 unclassified tumors (83% success rate). A confident diagnosis was made for 38/45 tumors (84%). Additionally, potential treatment targets were identified in 21/45 tumors (47%). Theoretical comparison with alternative assays demonstrated that WGTS was uniquely capable of detecting critical diagnostic findings in 15/38 tumors (39%). This work supports augmenting histopathology and standard molecular pathology with WGTS in the classification of difficult-to-diagnose tumors.

  Study EGAS00001008112

• Whole exome sequencing of pretreatment gastric and gastroesophageal junction tumors

  This set contains 40 bam files with whole exome sequencing data from 20 patients included in the PANDA study treated with 1 cycle of monotherapy atezolizumab and 4 cycles atezolizumab plus chemotherapy (docetaxel, oxaliplatin and capecitabine). Tumor DNA was isolated from tumor samples and germline DNA was isolated from PBMCs, which was used for whole exome sequencing.

  Dataset EGAD50000000242

• Neutrophil RNA-seq BAM files from 5 control donors and 5 patients with RSV

  This dataset contains RNA sequencing (RNA-seq) BAM files generated from neutrophils isolated from 10 healthy donors. Samples were collected from peripheral blood and processed for transcriptomic analysis. Sequencing was performed using Illumina technology, and reads were aligned to the human reference genome. These data enable analysis of baseline gene expression in human neutrophils.

  Dataset EGAD50000002668

• Microarray Gene Expression Data from Early Skin Biopsies of a Secukinumab Clinical Trial in Psoriasis

  The phase II clinical study CAIN457A2223 (NCT01537432) was designed to evaluate the proportion of patients achieving reversal of chronic plaque psoriasis at weeks 4 and 12 following multiple doses of secukinumab, administered subcutaneously, compared to placebo. 36 patients were enrolled in this study, with 24 being randomly assigned to the treatment arm and 12 to the placebo arm. Starting from week 13, all patients received multiple doses of secukinumab up to week 52 to study long term effects of secukinumab. The microarray gene expression data deposited in this dbGaP study are derived from the early (baseline to week 12) skin biopsies of this clinical trial.

  Study phs001688

• DNA methylation in rhabdomyosarcoma PDX and PDX-derived primary cells

  Conditions to maintain primary tumor cells in culture are largely unknown for most tumor entities including rhabdomyosarcoma. In this collaborative study with Dr. Beat Schäfer's laboratory, we performed DNA methylation profiles of rhabdomyosarcoma patient-derived xenograft (PDX) and their matching PDX-derived primary cells (PPC), where the PPCs were developed and maintained under optimized culture conditions. We further compared DNA methylation profiles between these PDXs and PPCs. Exome sequencing and copy number analysis between these rhabdomyosarcoma PDXs and PPXs were also carried out. These analyses may help us to evaluate a feasibility of in vitro profiling of primary rhabdomyosarcoma cells from a genomic perspective.

  Study phs002051

• Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

  We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

  Dataset EGAD00001006884

• Fecal microbiome of T2D patients undergoing semaglutide or empagliflozin treatment

  The gut microbiome has been shown to be affected by the use of many human-targeted medications, and the interaction can be bidirectional. This has been clearly demonstrated for type 2 diabetes medications that have been in clinical use for several decades. However, the bidirectional effects of novel type 2 diabetes drugs semaglutide, empagliflozin, and the gut microbiome have yet to be clearly described. We investigated the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, we analyzed whether the pre-treatment gut microbiome can predict the treatment efficacy. Twenty subjects (10 women and 10 men) were enrolled in the study between November 2019 and January 2023 from the University of Tartu Hospital, Tartu, Estonia. All participants had been diagnosed with type 2 diabetes. The study group taking semaglutide included 6 women and 4 men, and the group prescribed empagliflozin included 4 women and 6 men. Gut microbiome fecal samples donated at four timepoints (Baseline, Month 1, Month 3; Month 12) were studied using 16S ribosomal RNA gene sequencing and analysis.

  Dataset EGAD50000000756

• Single cell transcriptional evolution of myeloid leukaemia of Down syndrome – scRNA

  Abstract: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), and via a conserved sequence of mutations. Here, we examined the relationship between the genetic and transcriptional evolution of ML-DS from a rich collection of primary patient samples through single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We distilled the transcriptional consequence of each genetic step in the evolution of ML-DS, showing that TAM-defining GATA1 mutations account for most of the ML-DS transcriptome, including those of progressive disease. This transcriptional backbone may thus represent a common vulnerability in ML-DS. We extracted the transcriptional difference between TAM and ML-DS which, unexpectedly, reflected features shared across childhood leukaemia. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations directly from patient samples.

  Dataset EGAD00001015452

• Genome-wide association study for Bladder Cancer Risk

  This study funded by the National Cancer Institute (NCI) involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to bladder cancer. This bladder GWAS has led to the discovery of three novel regions in the genome associated with bladder cancer risk. Cases were defined as individuals having histologically confirmed primary carcinoma of the urinary bladder, including carcinoma in situ (ICD-0-2 topography codes C67.0-C67.9 or ICD9 codes 188.1-188.9). Scan data were obtained from two case-control studies carried out in Spain and the United States (specifically, those in the Maine and Vermont components of the New England Bladder Cancer Study) and three prospective cohort studies in Finland and the United States (specifically Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, and The American Cancer Society Cancer Prevention Study II Nutrition Cohort). We used data from 591,637 single nucleotide polymorphisms 3,532 affected individuals (cases) and 5,119 controls of European descent and replication including 8382 cases and 48275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P ≈ 8 x 10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10-11) on maps to CCNE1 and rs11892031 (P = 1 x 10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3 (Rothman N et al., Nature Genetics, 2010, PMID: 20972438). Through meta-analysis with the MD Anderson Texas Bladder Cancer Study (TXBCS), we also identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22) (Garcia-Closas M et al, Human Molecular Genetics, 2011) For NCI-GWAS2, we performed genotyping on cases and controls for the New Hampshire component of the New England Bladder Cancer Study (NEBCS-NH). For the majority of new bladder cancer cases, we genotyped only cases from four case-control studies, the Los Angeles Bladder Cancer Study (LABCS), the French Center for Research on Prostate Diseases (CeRePP), the French Bladder Study (FBCS) and the Brescia Bladder Cancer Study (BBCS). We used existing control data from four cohort studies already genotyped and subjected to rigorous quality control metrics: the European Prospective Investigation Into Cancer and Nutrition Study (EPIC), Womens Health Initiative (WHI), Health Professionals Follow-up Study (HPFS), Nurses Health Study (NHS), which have been a part of Cancer Genetic Markers of Susceptibility (CGEMS). Meta-analysis of NCI-GWAS1, NCI-GWAS2 and a previously reported GWAS TXBCS-GWAS along with taqman replication, identified two new loci: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 X 10(-7)); these require further studies for confirmation (Figueroa J et al, Human Molecular Genetics, 2013).

  Study phs000346