Search Results - EGA European Genome-Phenome Archive

Genome-wide NanoRCS sequencing of cfDNA and ctDNA from liquid biopsies of healthy individuals and cancer patients

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 developed 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 individuals, Esophageal cancer patients and Granulosa cell tumor patients and ascites of Ovarian cancer patients. We also sequenced these samples on Illumina Novaseq, to compare the two techniques.

Study EGAS50000000154

Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis

Adenomatous polyposis confers an increased risk of colorectal cancer development. Here, we investigated probably underlying predisposition variants in patients with suspected colorectal polyposis without variants in APC and MUTYH genes by whole exome sequencing (WES). Twenty-seven patients were included and subjected to germline WES. After filtering out variants for sequencing quality, variant allele fraction frequency, and population frequency, variants were manually prioritized by the ACMG criteria. Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 patients). This study gives information of probably associated polyposis variants in Brazilian patients without germline pathogenic variants in APC and MUTYH genes, supporting the utilization of next-generation sequencing for screening in these patients beyond these genes.

Study EGAS50000000591

RNA sequencing data from patient derived colorectal cancer organoids

This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The pipeline was utilized to analyze RNA-seq data from ten patient-derived colorectal cancer (CRC) organoids, representing seven microsatellite stable (MSS) and three microsatellite instable (MSI) tumors. The goal was to explore the ncTSA landscape in CRC, particularly in MSS cases, which typically exhibit low tumor mutational burden and limited response to current immunotherapies. The study identified comparable ncTSA burdens across MSI and MSS tumors, suggesting new avenues for immunotherapy targeting non-canonical antigens in CRC. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

Study EGAS50000000685

RNAseq samples of patients with anti-PD-1 resistant HNSCC from a non-randomized, open-label phase 1b clinical trial

Immune checkpoint blockade (ICB) is an effective treatment for a subset of patients with head and neck squamous cell carcinoma (HNSCC); however, the majority remain refractory. In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC who had progressed on ICB were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days, in combination with durvalumab and tremelimumab. The primary objective was to determine the biologically effective dose of 5-aza. In this study, RNA sequencing (RNA-seq) was performed on baseline and on-treatment samples from eight participants, and transcriptomic changes were analyzed to assess the impact of low-dose 5-aza treatment.

Study EGAS50000000728

Clinical validity of post-surgery circulating tumor DNA (ctDNA) in stage III colon cancer patients treated with adjuvant chemotherapy: the PROVENC3 study

The PROVENC3 study aimed to determine the clinical validity of post-surgery ctDNA testing in patients with stage III colon cancer treated with adjuvant chemotherapy (ACT). Blood was collected pre-surgery, post-surgery and post-adjuvant chemotherapy. Tumor-informed plasma ctDNA detection was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), white blood cell germline DNA (40x) and plasma cell-free DNA (30x). These raw WGS data for 209 patients are shared in .cram format in this EGA submission. For 196/209 of these patients there is overlapping FFPE tumor RNA sequencing data available, shared in .fastq format in this EGA submission.

Study EGAS50000000804

DCIS Whole Exome & Whole Genome Sequencing Data

Primary DCIS and recurrent DCIS/IBC (total n=82, ipsilateral n=78 and contralateral n=4) as well as non-recurrent DCIS (n=32) cases were identified through hospital databases from Royal Melbourne Hospital (RMH), Nottingham City Hospital (UK), the LifePool cohort and Peter MacCallum Cancer Centre (PMCC). All cases were micro-dissected from haematoxylin stained sections (range 4-20 sections) by manual micro-dissection to achieve >50% tumour tissue purity. DNA was extracted using the FFPE AllPrep kit (Qiagen, MD, USA). Depending on the success and timing of DNA extraction (Figure 1), cases were analysed by a targeted sequencing panel (n=46, samples pre-2020), whole exome sequencing (WES, n=67), or low-coverage whole genome sequencing (LCWGS). WES: DNA was processed by the Australian Genome Research Facility (AGRF) using the Twist Bioscience Human Comprehensive Exome v1 or v2 (Twist Bioscience HQ, South San Francisco, CA, USA) according to the Twist Target Enrichment Standard Hybridisation Protocol. Sequencing was performed on the Illumina NovaSeq 6000 with 150 bp paired-end reads for a median depth of 101.29x, range: 20.39-247x. Whole Genome Sequencing (WGS): Libraries for four paired samples with matched stromal DNA were made, processed and sequenced by AGRF using the IDT xGen Kit (USA) according to the manufacturer’s protocol, aiming to achieve 60x depth for tumour DNA and 30x for matched normal. File type: Paired-end FASTQ.

Dataset EGAD50000001846

Spatial transcriptomic data of breast cancer

Fastq files from spatial transcriptomic of breast cancer coming from 8 Breast cancer sections. Sample preparation: frozen BC samples were chosen based on tissue structure and RNA quality (RIN > 8). The “Visium Spatial Tissue Optimization Slide and Reagent Kit” (10X Genomics; #PN-1000193) was then used to optimize permeabilization conditions for BC tissues. Briefly, sections were fixed, stained and then permeabilized at different time points to capture mRNA, and the reverse transcription was performed to generate fluorescently labeled cDNA. The permeabilization time that resulted in the highest fluorescence signal with the lowest background diffusion was chosen. The best permeabilization time for BC tissue was 18 min. Cryostat sections of 10 μm of thickness were cut and placed on Visium Spatial Gene Expression slides (10X Genomics, PN-1000184). The slide was incubated for 1 min at 37°C, then fixed with methanol for 30 min at -20°C followed by Hematoxylin and Eosin (H&E) staining and images were taken under a high-resolution microscope. After imaging, the coverslip was detached by holding the slide in water and the slide was mounted in a plastic slide cassette. The spatial gene expression process, including tissue permeabilization, second strand synthesis and cDNA amplification, was performed according to the manufacturer’s instructions (10X Genomics; #CG000239). cDNA quality was next assessed using Agilent High sensitivity DNA Kit (Agilent, #5067-4626). The spatial gene libraries were constructed using Visium Spatial Library Construction Kit (10X Genomics, PN-1000184).

Dataset EGAD50000000322

RNA sequencing of periprostatic fat after a 6 month deep androgen deprivation therapy

Androgen deprivation therapy treated patients (n=11) were recruited from an open label neoadjuvant phase II study in which patients with high-risk disease received a ‘supercastration’ regimen consisting of degarelix 240/80 mg subcutaneously every four weeks; abiraterone acetate 500 mg orally daily titrating upwards every two weeks by 250 mg to a final dose of 1000 mg daily; bicalutamide 50 mg orally daily; and prednisolone 5 mg orally twice daily for a total of 6 months (Australian New Zealand Clinical Trials Registry 12612000772842). Untreated patients with similar pre-treatment characteristics were obtained from a prospective prostatectomy biorepository22,23. Prior to ligation of the dorsal venous complex and prostate pedicles, the anterior prostate was defatted and the specimen was removed immediately, placed in a sterile container and transferred on ice for long-term storage in the vapour phase of liquid nitrogen. A total of 50–100 µg of adipose tissue was separated from fresh frozen samples stored at −160°C. RNA was isolated using the Qiagen RNeasy Lipid Tissue Mini Kit and eluted in 35 µL nuclease-free water. 0.5–1 µg of total RNA was used as the input for cDNA library synthesis using TruSeq RNA Sample Prep Kit v2 (Illumina), and libraries were constructed according to manufacturer’s instructions. Samples were sequenced on a HiSeq 2500 (Illumina) using 101 base paired-end chemistry, aiming for 50 million mapped paired-end reads per sample.

Dataset EGAD00001004971

May 2021 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies, Genome Sciences Center, B.C. Cancer Agency as part of the International Human Epigenome Consortium.

May 2021 data update (fastq) for reference epigenomes generated at Centre for Epigenome Mapping Technologies (Canadian Epigenetics, Environment and Health Research Consortium), Genome Sciences Center, B.C. Cancer Agency, Vancouver, Canada as part of the International Human Epigenome Consortium.

Dataset EGAD00001008100

WGS_of_healhy_mesothelial_cells_and_primary_mesothelima_cell_lines

Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, here we aim at performing WGS of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

Study EGAS00001005559

GM adipose tissue study

The Greek Metabolic (GM) adipose study was carried out in 106 individuals living in Greece and consists of genotyping data (chip), RNA-Seq and ATAC-Seq (for a subset of individuals) data from paired biopsies of Subcutaneous and Visceral adipose tissue. eQTL mapping was performed to study gene regulation and findings compared to those from adipose tissue GTEX data. The focus of this project was to study an underexplored population living in different environmental conditions in order to reveal novel regulatory effects for genes that shape complex traits and disease risk. Our results highlight the utility of modest-sized studies in adding to our understanding of the molecular basis of complex traits and to the identification of mechanisms that drive disease in specific tissues.

Study EGAS00001007126

Integrative analysis of small cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype. We conducted integrated analysis of genome sequencing, transcriptome, and copy number analysis and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Evidence for inactivation of TP53 and RB1 was found in all sequenced cases. Furthermore, we identified recurrent mutations in CREBBP, EP300, and MLL, observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 locus. As a major feature of SCLC we found mutation in histone modifying genes, observed genome alterations that are therapeutically tractable, and provide a framework for identifying biologically relevant genes in the context of a high mutation rate. Peifer et al., 2012, Nature Genetics.

Study EGAS00001000299

Cell motility and migration as determinants of stem cell efficacy

Limited stem cell migration capacities and undirected homing hamper their therapeutic efficacy. We report here the novel technology to isolate stem cell subpopulations with high migration potential. Hereby, we identified podoplanin-dependent stem cell mobility as important mechanism for their in vivo homing capacities and therapeutic efficacy as validated in preclinical models of Alzheimer´s disease and mouse glioma. In vivo applications of highly migrating stem cells resulted in remarkable improvement of targeted homing and engraftment rates. Moreover, animals receiving highly migrating stem cells showed higher recovery rates compared to unselected stem cells. This novel technology provides useful tool to improve therapeutic efficacy of stem cells and give insights into stem cell subpopulations heterogeneity with the potential of general applicability for cellular therapies.

Study EGAS00001002478

Targeting PTPRK-RSPO3 colon tumours promotesdifferentiation and loss of stem-cell function

Colorectal cancer remains a major unmet medical need, promptinglarge-scale genomics efforts in the field to identify moleculardrivers for which targeted therapies might be developed. Wepreviously reported the identification of recurrent translocationsin R-spondin proteins present in a subset of colorectal tumours.Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion positivehuman tumour xenografts inhibits tumour growth andpromotes differentiation. Notably, genes expressed in the stem-cellcompartment of the intestine were among those most sensitive toanti-RSPO3 treatment. This observation, combined with functionalassays, suggests that a stem-cell compartment drives PTPRK-RSPO3colorectal tumour growth and indicates that the therapeutictargeting of stem-cell properties within tumours may be a clinicallyrelevant approach for the treatment of colorectal tumors.

Study EGAS00001001462

Sampling of multi-centric lower grade glioma influences management and provides insight into gliomagenesis

Rare multicentric lower-grade gliomas (LGG) represent a unique opportunity to study the heterogeneity between distinct tumor foci in a single patient, and to infer their origins and parallel patterns of evolution. In this study, we integrate clinical features, histology and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the two lesions. We show that each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors suggesting that comprehensive sampling of these lesions can significantly alter diagnosis and management.

Study EGAS00001002495

Integrative_Oncogenomics_of_multiple_myeloma

We used targeted capture and massively parallel sequencing of exomes of CD138 purified plasma cells and matched somatic DNA from 17 patients with Multiple Myeloma. For each patient, an early tumor sample (at diagnosis) and a late one (at relapse) were available. For few of them, an additional late sample (2nd progression) was present. In total, the study has 52 samples. 1044 variants were validated by 454 sequencing. The present study will validate an additional 4630 variants by targeted pull-down and sequencing. All 52 samples will be indexed and then will be pre-pooled in groups of 5 or 6. The sequence capture will use 10 reactions. All samples will then be pooled and go thorugh one lane of HiSeq.

Study EGAS00001000244

Pilot_experiment_on_functional_genomics_in_osteoarthritis_RNA

The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of large joint (hip and knee) osteoarthritis which culminates in the need for total joint replacement (TJR). In this pilot we will assess the feasibility of the approach in the relevant tissue. We will obtain diseased and non-diseased tissue (cartilage and endochondral bone) following TJR, coupled with a blood sample, from 12 patients. We will characterise the 12 pairs of diseased and non-diseased tissue samples in terms of transcription (RNASeq) The pilot will help assess the feasibility of isolating sufficient levels of starting material for the different approaches, and will instigate the development of analytical approaches to synthesising the resulting data.

Study EGAS00001001203

A PROSTATE TUMORGRAFT PANEL TO ACCELERATE PRECISION MEDICINE

The management of advanced prostate cancer (PCa) has strongly evolved in the last decade with the introduction of the next generation of androgen receptor pathway inhibitors which have considerably improved patient outcomes. Most recently, the investigation of genomic landscape has provided targetable molecular alterations such as homologous gene DNA repair defects correlated with response to PARP inhibitors. Despite these significant advances, while localized PCa is generally associated with favorable outcome, metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies.

Study EGAS00001007033

NOTCH1 fusion genes in pediatric T-cell lymphoblastic lymphoma hallmark a common high-risk subgroup with blood TARC levels as possible biomarker

T-cell lymphoblastic lymphoma (T-LBL) is a common pediatric malignancy accounting for approximately 20% of the non-Hodgkin lymphomas during childhood. Survival rates of T-LBL are ~80%, but outcome after relapse is dismal, with salvage rates reaching only ~15. Considering the extremely poor prognosis after relapse and absence of clinically relevant high-risk genetics, there is an urgent need for the identification of molecular risk factors and new prognostic biomarkers in T-LBL, as well as identification of new therapeutic strategies. In this study we present a novel entity of high-risk pediatric T-LBL patients characterized by previously unknown NOTCH1 gene fusions and highly elevated blood TARC levels

Study EGAS00001007703

Multi-region sequencing of RCC with VTT and metastasis using WES and RNAseq

This dataset contains multi-region sequencing of 16 RCC patients with venous tumor thrombus (VTT), 11 of which were either metastatic on diagnosis or recurred with metastasis. Whole exome sequencing is available for 94 samples across all 16 patients, including 1 matched normal sample per patient, 2-3 primary tumor samples per patient, 1-2 VTT samples per patient, and 0-3 metastasis samples per patient (metastatic lesions were only sampled for 8 of the 11 metastatic patients). RNAseq, generated by exome capture, is available for 67 samples across 12 patients, including 0-1 matched normal samples per patient, 3 primary tumor samples per patient, 0-1 VTT samples per patient, and 0-3 metastasis samples per patient (RNAseq was only available for 4 of the 8 patients from whom metastatic lesions were sampled).

Dataset EGAD00001008441

Integrative genome profiling in AML

AML emerges as a consequence of accumulating independent genetic aberrations that direct regulation and/or dysfunction of genes resulting in aberrant activation of signalling pathways, resistance to apoptosis and uncontrolled proliferation. Given the significant heterogeneity of AML genomes, AML patients demonstrate a highly variable response rate and poor median survival in response to current chemotherapy regimens. For the past 4 years we have conducted gene expression profiling on purified bone marrow populations equating to normal haematopoietic stem and progenitor cells from healthy subjects and patients with de novo AML in order to identify AML signatures of aberrantly expressed genes in cancer versus normal. We are now applying a series of bioinformatic methodologies combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostication of AML. Additionally, we use our AML signatures to unravel oncogenic signalling pathway activities in AML patients and test inhibitory drugs for these pathways inn preclinical therapeutic programmes. We consider that superimposing GEP and clinical data for our AML patient cohort with additional data on their mutational status will significantly improve the prognostic power of the study as well as unravel yet unknown mutations associated with aberrant signalling activities of oncogenic pathways.

Dataset EGAD00001001873

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

Brief SummaryThis randomized phase II trial studies the side effects of durvalumab and tremelimumab to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal (CRC) or non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic). Immunotherapy with durvalumab and tremelimumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.Detailed DescriptionPRIMARY OBJECTIVES:I. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 (durvalumab) and tremelimumab alone or with high or low-dose radiation in non-small cell lung cancer (NSCLC). (NSCLC Cohort) II. To compare the overall response (excluding the irradiated lesion[s]) between combined checkpoint blockade with MEDI4736 and tremelimumab alone or combined checkpoint blockade with low or high dose radiation. (NSCLC Cohort) III. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 and tremelimumab with high or low-dose radiation. (Colorectal Cohort) IV. To determine the overall response rate (excluding the irradiated lesion[s]) with combined checkpoint blockade with MEDI4736 and tremelimumab with either low or high dose radiation. (Colorectal Cohort)SECONDARY OBJECTIVES:I. To estimate median progression-free survival and overall survival. (NSCLC Cohort) II. To determine local control within the irradiated field(s) and abscopal response rates. (NSCLC Cohort) III. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells and overall response. (NSCLC Cohort) IV. To explore changes in PD-L1 expression, circulating T-cell populations, T-cell infiltration, ribonucleic acid (RNA) expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (NSCLC Cohort) V. To estimate median progression-free survival and overall survival. (Colorectal Cohort) VI. To determine local control within the irradiated field and abscopal response rates. (Colorectal Cohort) VII. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+ CD8+ T-cells and overall response. (Colorectal Cohort) VIII. To evaluate changes between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells induced by targeted low or high dose radiation. (Colorectal Cohort) IX. To explore changes in circulating T-cell populations, T-cell infiltration, RNA expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (Colorectal Cohort)OUTLINE: Patients are assigned to 1 of 2 cohorts. NOTE: This Study is only for Cohort 2. Please see phs003295 for Cohort 1COHORT 1: Patients with NSCLC are randomized to 1 of 3 arms.ARM A: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.ARM C: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses.COHORT 2: Patients with CRC are randomized to 1 of 2 arms.ARM A: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.After completion of study treatment, patients are followed for up to 12 weeks.Official TitleA Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC Conditions Metastatic Colorectal CarcinomaMetastatic Lung Non-Small Cell CarcinomaStage IV Colorectal Cancer AJCC v7Stage IV Lung Non-Small Cell Cancer AJCC v7Stage IVA Colorectal Cancer AJCC v7Stage IVB Colorectal Cancer AJCC v7 Intervention/Treatment Biological: DurvalumabRadiation: Radiation TherapyBiological: Tremelimumab Other Study ID Numbers NCI-2016-01325NCI-2016-01325 ( Registry Identifier ) (REGISTRY: CTRP (Clinical Trial Reporting Program))17-71910021 ( Other Identifier ) (OTHER: Dana-Farber - Harvard Cancer Center LAO)10021 ( Other Identifier ) (OTHER: CTEP) Molecular Technologies/AssaysIHCmIFOlinkCyTOFRNAseqWES

Study phs003294

A Multiethnic Genome-wide Scan of Prostate Cancer

Multiple GWA studies of prostate cancer conducted in European White populations are ongoing. These studies will continue to have a dramatic impact on our understanding of the contribution of common genetic variation on inter-individual susceptibility to this common cancer. Important questions that will remain unanswered, however, are whether all common risk alleles for prostate cancer will be revealed in studies limited to populations of European ancestry. A comprehensive examination of common genetic variation in men of Japanese, Latino, and African ancestry will be required to understand population differences in disease risk and to reveal the full spectrum of causal alleles that exist in these populations. Further, genetic and environmental diversity is likely to contribute to ethnic heterogeneity of genetic effects. Elucidating gene x gene and gene x environment interactions is also likely to provide knowledge that may be critical for understanding the contribution of genetic susceptibility to racial/ethnic disparities in prostate cancer incidence and for translating the findings from GWA studies into interventions. In this study we plan to undertake a genome-wide association study (GWAS) of prostate cancer in the Multiethnic Cohort (MEC) Study. We propose the following hypotheses: (a) that inherited DNA variation influences risk of prostate cancer; (b) that many of the causal alleles will be outside known "candidate genes" requiring an agnostic, comprehensive search; and (c) that performing this search in a multi-ethnic cohort is more powerful than a study limited to a single population to reveal the full range of causal alleles relevant to the U.S. population. The version 1 release of this dataset will include genotype data for the Japanese and Latino populations in the study. The version 2 release will include data for the African ancestry population along with the Japanese and Latino subjects. The version 3 release will include fully-cleaned genotype data for all three populations. 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 prostate cancer through large-scale genome-wide association studies of a well-characterized multi-ethnic cohort. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center and at the University of Southern California. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington. As an add-on to this GWAS we performed a targeted re-sequencing of all known prostate cancer risk loci in the samples from the MEC. Sequencing was performed in Dr. Reich's lab at Harvard Medical School.

Study phs000306

National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III)

The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is a nationally representative cross-sectional survey of the U.S. general population, which was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and conducted in 2012-2013. The NESARC-III's target population was the U.S. noninstitutionalized civilian population, 18 years and older, including residents of selected group quarters (e.g., group homes, workers' dormitories). Multistage probability sampling was used to randomly select respondents. Primary sampling units (PSUs) were individual counties or groups of contiguous counties, secondary sampling units (SSU) comprised groups of Census-defined blocks, and tertiary sampling units were households within SSUs. Finally, eligible adults within sampled households were randomly selected. Hispanics, Blacks, and Asians were oversampled and resulted in a total of 36,309 respondents. All respondents provided informed consent for survey participation. Data were adjusted for oversampling and screener - and person-level nonresponse, then weighted through post-stratification to represent the US civilian population based on the 2012 American Community Survey. These weighting adjustments were found to compensate adequately for nonresponse. Interviewer field methods involved initial structured home study, in-person training, ongoing supervision, and random respondent callbacks to verify data. The NESARC-III collected information on alcohol and drug consumption, alcohol use disorder, other substance use disorders (e.g., nicotine, cannabis and opioid), and associated physical and psychiatric adverse consequences. In addition to a full array of sociodemographic characteristics such as race/ethnicity, gender, age, risk and environmental factors including adverse childhood experiences (e.g., sexual, physical abuse and neglect) and family history for alcohol, drug use disorders and other psychiatric disorders (e.g., mood, anxiety, personality disorders and PTSD) were included (phenotypic variables=4,320). As part of the NESARC-III, 22,848 informative samples were genotyped on Affymetrix Axiom Exome Array consisting of 319,283 SNPs and 103,404 custom-selected SNPs Array (refer to the SNP annotation file). The latter array was selected based on the addiction associated genes, the results of 5 GWAS of alcohol and other psychiatric disorders, and animal models with addiction phenotypes. After filtering out poor quality SNPs using the standard Affymetrix pipeline there are 295,218 SNPs in the NESARC-III genetic data. The 22,848 subjects in this study were all deeply and consistently phenotyped via structured diagnostic interview. Controls group can be selected for specific disorders from a pool of all samples. Here are numbers of cases for major DSM-5 mental disorders in NESARC-III genetic data: Alcohol use disorder (7,075); Nicotine use disorder (6,641); Drug use disorder (2,570); Major depressive disorder (5,214); Persistent depression(1,429); Bipolar I (543); Anxiety disorders (4,226); PTSD (1,674); Personality disorders (4,014); Eating Disorders (457).

Study phs001590

eIMPACT Trial: Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients

Cardiovascular disease (CVD) is the #1 killer of American men and women, and its economic burden is substantial and on the rise. Adults with depression are at elevated risk of CVD events and poor CVD prognosis. Unfortunately, past clinical trials of depression treatments have not observed the anticipated cardiovascular benefits. A novel explanation for these null results is that the depression interventions in these trials, which all involved patients with preexisting CVD, were delivered too late in the natural history of CVD. Accordingly, the objective of this single-center, parallel-group, assessor-blinded randomized controlled trial was to determine whether successful depression treatment before, versus after, the onset of clinical CVD reduces CVD risk in depression. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized 1:1 to 12 months of the eIMPACT intervention (a modernized collaborative stepped care program involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). The primary outcome was endothelial dysfunction (brachial flow-mediated dilation) at 12 months, and the secondary outcomes were self-reported depressive symptoms (Hopkins Symptom Checklist-20), autonomic dysfunction (high-frequency heart rate variability), systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein), and platelet activation (β-thromboglobulin and platelet factor 4) at 12 months. The central hypothesis was that the eIMPACT intervention would improve endothelial dysfunction in depressed adults by decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. Primary results are posted to ClinicalTrials.gov at NCT02458690. The de-identified limited dataset available on BDC consists of only the individual phenotypic data needed to confirm this trial’s primary results – i.e., randomization status, primary and secondary outcome variables, and participant characteristics utilized in the hypothesis-testing models (age, sex, race, education, income, and systolic blood pressure). We also provide the SAS code to replicate the results of the hypothesis-testing models reported in Table 4 and Supplemental Tables 1-3 in the main outcomes paper (#2 in Selected Publications). Of note, the user will need to specify the file path for the dataset to run the SAS code. Instructions for requesting individual-level data are available on BDC at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BDC. For questions about availability, you may contact the BDC team at https://biodatacatalyst.nhlbi.nih.gov/contact.

Study phs003283

Heart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy - (HFN ATHENA-BioLINCC)

ObjectiveTo assess whether high-dose spironolactone treatment for patients with acute heart failure lowers natriuretic peptide levels and improves outcomes better than usual care.BackgroundAcute heart failure (AHF) accounts for more than a million hospitalizations in the United States annually. The role of low-dose mineralocorticoid receptors antagonists (MRAs) therapy as a neurohormonal antagonist is well established for the treatment of chronic heart failure and reduced ejection fraction. However, the role of high-dose MRA therapy in AHF remained uncertain. A previous clinical trial suggested that the benefits of high-dose MRA therapy in AHF included lower natriuretic peptide levels, less congestion, better renal function, and less need for an intravenous diuretic. The use of intravenous loop diuretics can intensify secondary hyperaldosteronism among AHF patients, and hyperaldosteronism directly contributes to diuretic resistance in AHF. Elevated aldosterone levels in AHF are associated with an increased risk of cardiovascular mortality and HF readmission. Hospitalizations for heart failure are associated with increased risk of mortality and/or readmission.The HFN-ATHENA trial was conducted to determine if mineralocorticoid receptor antagonists administered at high doses relieved congestion, decreased diuretic resistance, and mitigated the effects of adverse neurohormonal activation in AHF.SubjectsThe ATHENA trial enrolled 360 participants. Of these, 178 participants were randomized to usual care treatment (placebo or low-dose spironolactone) and 182 participants were randomized to high-dose spironolactone.DesignThe study intervention was initiated within 24 hours of patients receiving the first dose of intravenous diuretics. Participants not taking spironolactone at enrollment were randomized to 100 mg spironolactone or a placebo. Participants taking low-dose spironolactone before their hospital admission were randomized to 100 mg or 25 mg per day in the usual care treatment arm. Prescription of all other medications, including diuretics, was left at the discretion of the treating physician. The study drug was discontinued after 96 hours and further MRA use was left to the treating physician's discretion. The primary end point was the proportional change in the log NT-proBNP levels from randomization to 96 hours (or at the hospital discharge if the discharge occurred earlier than 96 hours). Secondary endpoints included: (1) a clinical congestion score; (2) dyspnea relief; (3) daily cumulative net urine output for up to 96 hours; (4) net weight change from baseline to 96 hours or discharge (whichever came first); (5) furosemide equivalents of the loop diuretic dosage at discharge; and (6) the development of in-hospital worsening HF, with signs and symptoms requiring additional therapy.ConclusionsThere was no significant difference in the primary or secondary endpoints between the high-dose treatment arm and the usual care treatment arm.

Study phs003506

Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 µm sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-naïve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

Study phs003865

Institute for Refractory Cancer Research (IRCR) Data Access Committee

Dac EGAC00001000272

DAC for study Hominin-specific NOTCH2 paralogs expand human cortical neurogenesis through regulation of Delta/Notch interactions.

Dac EGAC00001000816

Wargo Group Data Access Committee for Neodjuvant Immune Checkpoint Blockade in High-Risk Resectable Melanoma

Dac EGAC00001001008

DAC for study the impact of urbanization and diet on innate immune responses in healthy Tanzanians

Dac EGAC00001001531

Patient-derived tumor organoids for personalized medicine in a rare case of hepatocellular carcinoma with neuroendocrine differentiation.

Dac EGAC00001002458

Ultra-deep targeted sequencing for studying the accumulation of somatic mutations in cancer-free human skin

Study EGAS00001004279

Karolinska Institutet - Susanne Schlisio Lab

DAC for Susanne Schlisio Lab, Department of Oncology-Pathology, Karolinska Institutet, Sweden

Dac EGAC50000000603

MutationalPatterns2: The one stop shop for the analysis of mutational processes: DNA repair deletions

Study EGAS00001004789

Preliminary Results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT 2) Study

Study EGAS00001004964

Molecular evolution and clinical trajectories of prostate cancer identifies novel markers for risk stratification - additional data

Study EGAS00001004884

High coverage sequencing of a single sample can account for the problem of intratumor heterogeneity

Study EGAS00001004200

A capture-based next-generation sequencing panel for the molecular characterization of chronic lymphocytic leukemia

Study EGAS00001006975

CUPiD, a cfDNA methylation-based tissue-of-origin classifier for Cancers of Unknown Primary

Study EGAS00001007445

HC_genotyping

HC genotyping data for lead SNPs using Illuminia Global Array V2.0

Dataset EGAD00010002475

WES of TGA

Whole exome sequencing data for 381 TGA probands

Dataset EGAD00001005809

Genomic Sequencing of Triple Negative Breast Cancer - CUTseq data

CUTseq data for study EGAS00001008261

Dataset EGAD00001015684

NHLBI TOPMed - NHGRI CCDG: The BioMe Biobank at Mount Sinai

The IPM BioMe Biobank, founded in September 2007, is an ongoing, broadly-consented electronic health record (EHR)-linked clinical care biobank that enrolls participants non-selectively from the Mount Sinai Medical Center patient population. BioMe currently comprises >42,000 participants from diverse ancestries, characterized by a broad spectrum of longitudinal biomedical traits. Participants are enrolled through an opt-in process and consent to be followed throughout their clinical care (past, present, and future) in real-time, allowing us to integrate their genomic information with their EHRs for discovery research and clinical care implementation. BioMe participants consent for recall, based on their genotype and/or phenotype, permitting in-depth follow-up and functional studies for selected participants at any time. Phenotypic and genomic data are stored in a secure database and made available to investigators, contingent on approval by the BioMe Governing Board. BioMe uses a "data-broker" system to protect confidentiality. Ancestral diversity - BioMe participants represent a broad racial, ethnic and socioeconomic diversity with a distinct and population-specific disease burden. Specifically, BioMe participants are of African (AA), Hispanic/Latino (HL), European (EA) and other/mixed ancestry. BioMe participants are predominantly of African (AA, 24%), Hispanic/Latino (HL, 35%), European (EA, 32%), and other ancestry (OA, 10%). Participants who self-identify as Hispanic/Latino further report to be of Puerto Rican (39%), Dominican (23%), Central/South American (17%), Mexican (5%) or other Hispanic (16%) ancestry. More than 40% of European ancestry participants are genetically determined to be of Ashkenazi Jewish ancestry. With this broad ancestral diversity, BioMe is uniquely positioned to examine the impact of demographic and evolutionary forces that have shaped common disease risk. Phenotypes available in BioMe - BioMe has a high-quality and validated set of fully implemented clinical phenotype data that has been culled by a multi-disciplinary team of experienced investigators, clinicians, information technologists, data-managers, and programmers who apply advanced medical informatics and data mining tools to extract and harmonize EHRs. BioMe, as a cohort, offers a great versatility for designing nested case-control sample-sets, particularly for studying longitudinal traits and co-morbidity in disease burden. Biomedical and clinical outcomes: The BioMe Biobank is linked to Mount Sinai's system-wide Epic EHR, which captures a full spectrum of biomedical phenotypes, including clinical outcomes, covariate and exposure data from past, present and future health care encounters. As such, the BioMe Biobank has a longitudinal design as participants consent to make all of their EHR data from past (dating back as far as 2003), present and future inpatient or outpatient encounters available for research, without restriction. The median number of outpatient encounters is 21 per participant, reflecting predominant enrollment of participants with common chronic conditions from primary care facilities. Environmental data: The clinical and EHR information is complemented by detailed demographic and lifestyle information, including ancestry, residence history, country of origin, personal and familial medical history, education, socio-economic status, physical activity, smoking, dietary habits, alcohol intake, and body weight history, which is collected in a systematic manner by interview-based questionnaire at time of enrollment. The IPM BioMe Biobank contributed ~10,600 DNA samples for whole genome sequencing to the TOPMed program. Samples were selected for the Coronary Artery Disease (CAD) and the Chronic Obstructive Pulmonary Disease (COPD) working groups. Using a Case-Definition-Algorithm (CDA), we identified ~4,100 individuals with CAD (~50% women) and ~3,000 individuals as controls (65% women). In addition, we identified ~800 individuals with COPD (62% women) and 1800 individuals as controls (72% women). Another 600 BioMe participants with Atrial Fibrillation, all of African ancestry, were included.

Study phs001644

DMET Genes, Nicotine Metabolism and Prospective Abstinence

This study (DA033813; PI: Andrew W Bergen; PMID:26132489) includes samples from two laboratory studies of nicotine metabolism. The Pharmacokinetics of Nicotine Metabolism in Twins study (PKTWIN; PI: Gary E Swan; PMID: 15527659) was based on recruitment from a twin registry (PMID: 23084148). The Integrated Research Project on Tobacco Use and Dependence (IRP; PI: Gary E Swan; PMID: 14578134) was based on recruitment from a pedigree-based longitudinal study of risk factors for substance use, the Smoking in Families study (SMOFAM; DA03706; PI: Hy Hops). These two laboratory studies (PKTWIN and IRP/SMOFAM) served as the Stage I dataset to interrogate Drug Metabolizing Enzyme and Transporter genes with a targeted SNP array for association with the Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), an established biomarker of nicotine metabolism. In addition to the laboratory studies, samples from eight RCTs (PMID: 23249876) with the NMR and smoking-related measures used to test SNPs identified in Stage I (PMID: 26132489). In a third stage, a lung cancer meta-analysis database (PMID: 24880342) was used to assess association of SNPs identified in Stage II with lung cancer. The objectives of the study were to identify novel genes and SNPs contributing to nicotine metabolism (Stage I), and to validate PK SNPs associated with the NMR from individuals participating in a clinical laboratory protocol with the NMR obtained from treatment-seeking smokers, and then to investigate association with prospective smoking cessation (Stage II). This study built upon existing studies of nicotine metabolism and randomized trials of smoking cessation therapies. Enhanced knowledge of the genes influencing nicotine metabolism and prospective abstinence may help personalize smoking cessation treatment and risk assessment for smoking-related diseases. For Stage I, both subject [fixed-dose NMR, covariates (age, BMI, ethnicity, sex, smoking status, and hormone use), and pedigree relationships] and sample (common DMET SNP genotype, genotyping quality control) data are available in this accession. The analysis protocol, quality control summaries, summary genotype, summary phenotype, and analysis results are available for Stage I, II and III samples (PMID: 26132489). Extensive discussion of the prior CYP2A6 association literature with the NMR, abstinence, smoking heaviness and lung cancer risk is available (PMID: 26132489). The NMR has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

Study phs000931

A Genome-Wide Association Analysis in Angiotensin-Converting Enzyme (ACE) Inhibitor-Associated Angioedema and ACE Inhibitor-Exposed Controls; A Collaboration between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Center for Genomic Medicine

The purpose of this study is to identify genetic predictors of ACE inhibitor-associated angioedema. In addition to preventing the formation of the pressor angiotensin II, ACE inhibitors prevent the carboxyl-terminal degradation of the vasoactive substances bradykinin and substance P. Angioedema is hypothesized to result from defective amino-terminal degradation of bradykinin or substance P in patients in whom ACE is inhibited. For example, activity of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for the inactivation of substance P when ACE is inhibited, is decreased in patients with angioedema. In preliminary studies, we have identified SNPs in the DPP4 gene that associate with DPP-IV activity and, in blacks, with risk of angioedema. This project will use genome-wide genotyping to compare 250 cases and 568 ACE inhibitor-exposed control subjects (131 cases and 288 controls ascertained at Vanderbilt and 70 cases and 280 controls ascertained at the Marshfield Clinic). We plan a 2-stage analysis of associations between SNPs and angioedema - first, we will study DPP4 SNPs for association with angioedema and, second, we will explore associations using the full GWAS data set. Depending on the platform, additional DPP4 SNPs will be used to fully tag common genetic variants in both African American and European American samples. Based on the HapMap data, there are 14 tagging SNPs in people of European descent and 34 in Yoruba (selection criteria MAF>0.05 and r2>0.8). Cases were defined as having ACE inhibitor-associated angioedema if they had had swelling of the lips, throat, tongue or face while taking an ACE inhibitor but had never had angioedema while not taking an ACE inhibitor. For simplicity, intestinal edema was excluded. Control subjects were treated for at least 6 months with an ACE inhibitor without angioedema. Because black Americans are known to be overrepresented among patients with ACE inhibitor-associated angioedema, control subjects were prespecified to be 50% black American, 50% white American, and 50% female. At Vanderbilt, the medical history, including the history of angioedema, was confirmed by a research nurse or physician using a detailed case report form. Characteristics of Vanderbilt cases appear in the Table. At Marshfield, medical history will be confirmed by chart review. The Marshfield cohort is 98% white American and 57% female with a mean age of 47.2 years.

Study phs000438

DNA methylomes of monozygotic twins clinically discordant for multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms. In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins, and studied the impact of MS treatments on the DNA methylome. Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS). In addition, we performed whole genome bisulfite sequencing (WGBS) to profile CD4+ memory T-cells of a subset of four MS discordant MZ twins. Our results show that interferon treatment causes robust DNA methylation changes and several epigenetic biomarkers for interferon treatment response were identified. However, overall the PBMC-based methylomes of the MS discordant MZ twins were highly similar, since large systematic methylation differences (>5%) were absent in the data. This suggests that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Although not genome-wide significant, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history. WGBS analysis confirmed this DMP as a promising epigenetic biomarker for glucocorticoid treatment. In conclusion, this epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, epigenetic biomarkers for MS treatments were identified, revealing that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in future EWAS designs.

Study EGAS00001003147

Genetic Predictors of Adverse Radiotherapy Effects (Gene-PARE)

The goal of this study was to identify SNPs and CNPs that are associated with development of normal tissue toxicities resulting from radiotherapy for prostate cancer. The study population includes approximately 1,400 men treated with brachytherapy, external beam radiation therapy, or a combination of the two treatments, and assessed for adverse effects at baseline and following radiotherapy. Three toxicity endpoints were investigated using a two-stage GWAS approach: urinary morbidity, rectal bleeding and erectile dysfunction. The study sample was split into a discovery set (N=367) and a replication set (N=417), and an additional 647 samples, which were not part of this original cohort, were also included as an independent replication set. The replication set was developed via collaboration developed under the framework of the Radiogenomics Consortium (RGC). The long-term goal of this project, and other radiogenomics projects lead by the RGC, is two-fold: 1) Develop an assay capable of predicting which cancer patients are most likely to develop radiation injuries resulting from treatment with a standard RT protocol, and 2) Obtain information to assist with the elucidation of the molecular pathways responsible for radiation-induced normal tissue toxicities. These studies focus on multiple cancer types including prostate, breast, lung, and head and neck cancers.

Study phs000772

Joslin Study on the Genetics of Type 2 Diabetes

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

Study phs002959

Multicenter AIDS Cohort Study (MACS)

The Multicenter AIDS Cohort Study (MACS) - now part of the MACS-WIHS Combined Cohort Study (MWCCS) investigates the epidemiology of human immunodeficiency virus (HIV) infection among men who have sex with men. Over 7,000 participants volunteered for semiannual interview, physical examination, and laboratory testing across the 325 years of the study, in four metropolitan areas of Los Angeles, Chicago, Baltimore/Washington (DC) and Pittsburgh. The study aimed to identify risk factors for occurrence and clinical expression of the HIV infection, and to establish a repository of biologic specimens for future study. Study visits included detailed questions covering HIV-related symptoms and utilization of health services, demographic and psychosocial characteristics, a quality of life survey, a physical examination, a detailed form on medications used as prophylaxis and/or treatment, a neuropsychological screening and examination, blood samples to do measure hematologic variables including enumeration of T-cell subsets and HIV viral load and evaluate genetic risk factors via genome wide association studies using data generated using the Infinium Multi-Ethnic Global BeadChip genotyping array in all participants. Men who have sex with men, with and without HIV infection were enrolled in the MACS. MACS data continues to be available through the merged MWCCS cohort.

Study phs002226

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