Search Results - EGA European Genome-Phenome Archive

Predicting brain tumor recurrence: development and validation of a DNA-methylation based nomogram in meningioma

Our work is the first to demonstrate the transformative utility of integrating clinical and molecular factors for use beyond simple classification into the realm of individualized prognostication for any brain tumor. Using our developed and validated tools that are publicly available, clinicians will be able combine clinical and molecular factors to determine an individualized probability of recurrence for patients with meningiomas. This represents a major advance in the field of personalized medicine for neuro-oncology, and the use of this tool can help clinicians overcome one of the most challenging limitations we face when treating patients with meningiomas.

Study EGAS00001003490

Volasertib preclinical activity in high-risk hepatoblastoma

Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

Study EGAS00001004827

Molecular response of AML blasts to Aza-treatment.

Azacytidine (Aza) treatment is effective in some patients with acute myeloid leukemia (AML). Clinical observations suggest that DNMT3A-mutant patients represent a subgroup of AML patients that responds particularly well to Aza-treatment. Data coming from a mouse model support this finding and we have already generated molecular data suggesting a molecular pathway involved in Aza-response in DNMT3A-mutant AML patients. We now aim to validate these findings in primary AML-blasts. To this end, we have FACS-sorted blasts from patients with AML prior to and under Aza-treatment and plan to correlate pre-treatment as well as on-treatment methylomes to clinical Aza-response.

Study EGAS00001004825

A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus.

Uveal melanoma, a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. A genome-wide association study of 259 uveal melanoma patients compared to 401 controls all of European ancestry revealed a candidate locus at chromosome 5p15.33 (region rs421284: OR = 1.7, CI 1.43-2.05). This locus was replicated in an independent set of 276 cases and 184 controls. In addition, risk variants from this region were positively associated with higher expression of CLPTM1L. In conclusion, the CLPTM1L region contains risk alleles for uveal melanoma susceptibility, suggesting that CLPTM1L could play a role in uveal melanoma oncogenesis.

Study EGAS00001002334

Chracterising_cellur_pathways_underlying_CD3_CD28_activation_of_human_CD4__cells

We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001002438

'KOREAN' never-smoker female adenocarcinoma RNA-seq

Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

Study EGAS00001003789

Detection of Cancer Mutations by Urine Liquid Biopsy in Bladder Cancer Patients

The management of bladder cancer faces multiple challenges concerning the diagnostics and fol-low-up approaches. The standard diagnostic test is invasive cystoscopy. Urine cytology and re-cently proposed urine-based biomarkers still could not replace cystoscopy, thus prompting calls for improvements. Here, we explore urine liquid biopsy to detect cancer mutations for therapeutic and prognostic assessment and subsequently evaluate the utility of urine as a suitable specimen in diagnosing bladder cancer. Our findings show that the analysis of pre-and post-operative urine enables the characterization of specific tumor mutations, which can be used to diagnose and evaluate a patient’s prognosis and therapy response.

Study EGAS00001005758

Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocarcinogenesis

Infection by Hepatitis B Virus (HBV) is the main risk factor for Hepatocellular Carcinoma (HCC) worldwide. HBV can directly drive carcinogenesis through integrations in human genome. This integrative analysis of a French cohort of 190 patients mainly coming from Europe and Africa provides a deep characterization of HBV integrations, in relation with viral and host genomics and clinical features. Clonal HBV integrations directly contribute to HCC development through alterations of cancer driver genes, either at distance when co-localizing with copy number alterations, either locally through viral Enhancers. Together, this analysis gives new insights on HBV-associated driver mechanisms involved in hepato-carcinogenesis.

Study EGAS00001004629

Single-cell roadmap of immune cell responses in chronic myeloid leukemia

To study the innate and adaptive immune responses in CML, we profiled 25 samples from CML patients including samples at diagnosis (n = 7, N = 9, where n is the number of subjects and N the number of samples if different from n) and before and after TKI-cessation with imatinib (n = 6, N = 15) with paired single-cell RNA and T cell receptor (TCR) αβ chain sequencing (scRNA+TCRαβ-seq) and compared our data to different cancers (n = 29) and healthy donors (n = 7). This dataset contains the samples from before and after TKI-cessation, please see the manuscript for info related to the other datasets.

Study EGAS00001005044

RNA sequencing data of 257 samples from the CORALLEEN trial

Early-stage Luminal B breast cancer is frequent and is a major cause of breast cancer death due to its poor prognosis. Our proposal aims to study the biology behind the sensitivity and resistance of Luminal B breast cancer to chemotherapy (CHT) or a non-CHT regimen composed of hormone therapy in combination with ribociclib, a CDK4/6 inhibitor. To accomplish this, we first completed the SOLTI-1402 CORALLEEN phase II trial, a study where 106 patients with early-stage Luminal B breast cancer were randomized to standard neoadjuvant CHT for 6 months, or neoadjuvant letrozole and ribociclib for 6 months. After treatment, patients underwent surgery. The primary results of the study, which showed that the response rate to letrozole+ribociclib was similar to CHT, was reported (Prat et al; Lancet Oncol). Tumor biopsies were available at baseline, week 3 and surgery. A total of 257 samples were analyzed using the Illumina TruSeq Stranded Total RNA w/Ribo Zero Gold with MiSeq in TGL (Sequencer NovaSeq S4/PE/100x)

Dataset EGAD00001010121

Timing the landmark events in the evolution of clear cell renal cell cancer

Clear cell renal cancer is characterized by near-universal loss of the short arm of chromosome 3 (3p). This event arises through unknown mechanisms, but critically results in the loss of several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cancer (ccRCC) recruited into the Renal TRACERx study. We find novel hotspots of point mutations in the 5'-UTR of TERT, targeting a MYC-MAX repressor, that result in telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. Using molecular clocks, we estimate this occurs in childhood or adolescence, generally preceding emergence of the most recent common ancestor by years to decades. Similar genomic changes recent common ancestor by years to decades. Similar genomic changes are seen in inherited kidney cancers. Modeling differences in age-incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Targeting essential genes in deleted regions of chromosome 3p could represent a potential preventative strategy for renal cancer.

Dataset EGAD00001003445

Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers: multi-timepoint exome sequencing of a single patient's disease

This dataset is a time-series of EGFR-mutant NSCLC clinical specimens from an individual patient profiled using tumor-based whole exome sequencing and the data is in BAM format. DNA was extracted from FFPE for primary tumor and frozen tumor tissue samples and matched non-tumor tissue using the Qiagen Allprep DNA/RNA Mini Kit. The library preparation protocol was based on the Agilent SureSelect Library Prep and Capture System. DNA was resuspended in a low TE buffer and sheared (Duty Cycle 5%; Intensity 175; Cycles/Burst: 200; Time: 300s, Corvaris S2 Utrasonicator). Bar-coded exome libraries were prepared using the Agilent Sure Select V5 library kit per manfucaturer’s specifications. The libraries were run on the HiSeq2500. Raw paired end reads (100bp) in FastQ format generated by the Illumina pipeline were aligned to the full hg19 genomic assembly obtained from USCS, gencode 14, using bwa version 0.7.12. Picard tools version 1.117 was used to sort, remove duplicate reads and generate QC statistics. Tumor DNA was sequenced to median depth of 303X (range 114.39-383.41) and the matched germline DNA to average depth of 231.65.

Dataset EGAD00001003769

The landscape of somatic mutation in normal colorectal epithelial cells

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic events and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ~1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

Dataset EGAD00001004192

P647 Targeted resequencing project

In collaboration with Dr Robert Semple we have identified a family harbouring an autosomal dominant variant, which leads to severe insulin resistance (SIR), short stature and facial dysmorphism. This family is unique within the SIR cohort in having normal lipid profiles, preserved adiponectin and normal INSR expression and phosphorylation. DNA is available for 7 affected and 7 unaffected family members across 3 generations. All 14 samples have been genotyped using microsatellites and the Affymetrix 6.0 SNP chip. Linkage analysis identified an 18.8Mb haplotype on chromosome 19 as a possible location of the causative variant. However, Exome sequencing of 3 affected and 1 unaffected family members has not identified the causative variant suggesting the possibility of an intronic or intergenic variant in this region or elsewhere in the genome. We propose to conduct whole genome sequencing of 5 members of the pedigree at a depth of 20X. The chosen samples are two sets of parents plus one member of an unaffected branch of the pedigree who shares the risk haplotype on chromosome 19. Sequencing of the two sets of parents will be used along with the genome-wide SNP data to impute 4 affected children giving an effect sample size of 6 affected individuals.

Dataset EGAD00001000383

Regulatory and Effector T cells in Oral Immunotherapy for Food Allergy

This study consisted of a clinical trial for peanut oral immunotherapy (OIT) and a follow-up project (see below). Patients were included from 2013-2015, and samples from the last timepoints were collected in 2017. The study focused on peanut-specific CD4+ T cell responses before, during, and after OIT with peanut protein. We analyzed T cell gene expression, cytokine production, and T cell receptor β (TCRβ) and TCRα clonotypes, both in bulk T cell populations and single cells, and sought to correlate these data with differences in clinical sensitivity between peanut-allergic patients before OIT, and with differences in clinical outcome after OIT. The goal was to better understand the role of peanut-specific effector and regulatory T cells in peanut allergy and tolerance, which may inform more effective therapies (e.g., OIT combined with biologicals, probiotics, or adjuvants) in the future. Tolerance Following Peanut Oral Immunotherapy (PNOIT2, NCT01750879): The unifying objective of this project is to determine whether peanut oral immunotherapy (PNOIT)-induced clinical tolerance in the context of food allergy is significantly associated with the expansion of a specific regulatory T cell subset (CD45RA-, CD25++, FoxP3+ +) that is thought to be inducible in the gut-associated lymphoid compartment and associated with immunological tolerance. The hypothesis of the study is that the induction of Treg cells will be associated with clinical tolerance. The investigators will measure the change from baseline of induced Treg cells as a frequency of total CD4+ T cells during active treatment and compare that between participants who achieve significant clinical tolerance and those who do not. High Threshold Peanut Challenge Study (PAID-UP, NCT02698033): This protocol was designed to better characterize a sub-population of peanut-sensitized individuals who may be non-allergic, despite significant sensitization, or who may be allergic, but at high threshold doses. By specifically targeting participants who met the initial screening criteria of an earlier study, NCT01750879, but failed to react during the pre-treatment 443 mg challenge to peanut, the investigators anticipate that they will identify individuals who have become spontaneously tolerant, despite persistent sensitization. The investigators might also find that clinical sensitivity persists but only with higher thresholds, or that sensitivity has increased (or is variable) since the previous allergen exposure. By repeating food challenges through to a full serving dose (7.4 gram), the investigators will distinguish participants who react only at higher doses from those who were not truly peanut-allergic, address whether their sensitivity has changed, and have the opportunity to further investigate their immune response to peanut allergen. Methods: Peripheral blood mononuclear cells were isolated from patient blood samples, and stimulated with peanut protein. Peanut-activated CD4+ T cells were sorted based on the activation marker CD154. For a more recent study, the activation marker CD137 was used as well. Total RNA from peanut-activated CD154+ and resting CD154- CD69- T cells was used for cDNA synthesis and amplification (SMARTer ultra low input RNA kit for sequencing - v3; Clontech Laboratories). Libraries were prepared and sequenced on the Illumina HiSeq platform, at a read depth of approximately 30 million reads per sample. Genomic DNA from CD154+ and CD154- CD69- T cells was used to amplify and sequence the TCRβ CDR3 regions (immunoSEQ assay; Adaptive Biotechnologies). The immunoSEQ approach generates an 87 base-pair fragment capable of identifying the VDJ region spanning each unique CDR3. Amplicons were sequenced using the Illumina NextSeq platform. Using a baseline developed from a suite of synthetic templates, primer concentrations and computational corrections were used to correct for the primer bias common to multiplex PCR reactions. Raw sequence data were filtered on the basis of TCRβ V, D, and J gene definitions provided by the IMGT database (www.imgt.org) and binned using a modified nearest-neighbor algorithm to merge closely related sequences and remove both PCR and sequencing errors. For single-cell analysis, we aimed to recover TCR variable sequences from high-throughput single-cell libraries generated by popular platforms such as SeqWell and DropSeq. We paired TCR information with T cell single-cell RNA sequencing results from patients undergoing peanut OIT to show clonal expansion-related T cell phenotypes.

Study phs001897

CIDR, NCI, NIDA Sequencing of Targeted Genomic Regions Associated with Smoking

This study includes samples from two projects: Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: Laura Bierut) and Genetic Study of Nicotine Dependence in African Americans (AAND; PI: Laura Bierut and Eric Johnson). The majority of the COGEND subjects included in the current study overlap with the two datasets already available on dbGaP. GWAS data are available for COGEND subjects through the Study of Addiction: Genetics and Environment (SAGE), dbGaP study accession phs000092. It should be noted that the case definition in the SAGE study is DSM-IV alcohol dependence. GWAS data are available for additional COGEND subjects through The Genetic Architecture of Smoking and Smoking Cessation, dbGaP study accession phs000404. The overall goal of this project is to apply deep sequencing to key genomic regions associated with nicotine dependence in order to accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence. The sample includes unrelated cases and controls of European American and African American descent. Cases are defined by a commonly used definition of nicotine dependence, a current score of 4 or more (maximum score of 10) on the Fagerstrom Test for Nicotine Dependence (FTND). Control status is defined as an individual who smoked at least 100 cigarettes during their lifetime, yet never became dependent (lifetime FTND<2). By selecting controls who smoked cigarettes, we focus on those genetic effects that are specific to the development of nicotine dependence. COGEND: COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal was to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design was a community based case-control study. Nicotine dependent cases and non-dependent, smoking controls were identified and recruited from Detroit and St. Louis. More than 54,000 subjects aged 25-44 years were screened by telephone; more than 3,100 subjects were personally interviewed; and more than 2,900 subjects donated blood samples for genetic studies. AAND: AAND was initiated in 2009 to identify and characterize genetic determinants of nicotine dependence in a large African American population. Community-based recruitment of approximately 100,000 people was conducted to ascertain 1,000 African American nicotine dependent cases and 1,000 African American non-dependent, smoking controls. All subjects were between the ages of 25-44. Subjects were screened by telephone; if they qualified as a case or control, they completed the same interview that was used in COGEND and donated a blood sample. Both studies (COGEND and AAND) included measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, and educational attainment using the Semi-Structured Assessment for the Genetics of Nicotine Dependence. Information on nicotine dependence, as assessed by the Fagerstrom Test for Nicotine Dependence (FTND) is available for all subjects. In addition, participants also completed the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68; Piper et al, 2004). All subjects were assessed in person by trained research assistants.

Study phs000813

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

We report a significant advance in Moyamoya disease (MMD) research through our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. Moyamoya Disease (MMD) is a rare cerebrovascular disorder characterized by unilateral or bilateral progressive stenosis or occlusion of the internal carotid artery, with frequent involvement of the anterior cerebral artery and the middle cerebral artery (MCA). Fragile collateral vessels subsequently develop and are particularly prone to hemorrhage. MMD patients are usually diagnosed angiographically following presentation of developmental delays, seizures, migraines, ischemia, and/or hemorrhage. The most common approach to re-establish normal blood flow is bypass surgery. While some progress has been made in identifying disease-associated genes, the underlying disease biology is not well understood. Moyamoya disease (MMD) is a rare cerebrovascular disease. Our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics has led to a significant advance in the field. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. The 125 ethnically diverse, unrelated MMD patients were matched based on sex and broad ethnic category to 125 controls. Control DNA from the 1000 Genomes project was used to design a control Library by Personalis. 125 controls were selected from this Personalis Control DNA Library for our study. (The 1000 Genomes Project Consortium 2012). Genomic DNA was extracted using the Gentra Puregene kit (Qiagen, Valencia, CA). Libraries were prepared from approximately 3 µg of high quality genomic DNA (50-200 ng/µl) using Illumina TruSeq Genomic DNA High throughput Sample Prep Kits (Illumina, San Diego, CA) and exome enrichment (targeting 62Mb) was accomplished using the TruSeq Exome Target Enrichment kit (Illumina, San Diego, CA), all according to manufacturer's protocols. Target enrichment validation was confirmed by determining the concentration of the library by PicoGreen-based quantitation. Library yields ranged from 100-1000ng of DNA, a portion of which was run on the Bioanalyzer HS DNA chip (Agilent, Santa Clara, CA), with an average size of 300-550nt for DNA fragments. Exome Sequencing. Sequencing was performed using Illumina Hiseq2000 or HiSeq2500 sequencers with single lane, paired-end 2X100bp reads. DNA fragments were generated and amplified using Clonal Single Molecule Array technology (Illumina, San Diego, CA). The sequences were determined using the Clonal Single Molecule Array and Sequencing-by-Synthesis using Illumina's instrumentation and Reversible Terminator Chemistry. Each sequencing lane interrogated the DNA sequences of a pool of 3 individual sample libraries each carrying a unique index. Sequencing reads of at least 2x100bp in length for a total of approximately 8 Gb of sequence data were generated for each sample.

Study phs001700

STAMPEED: Northern Finland Birth Cohort 1966 (NFBC1966)

The Northern Finland Birth Cohorts program (NFBC) was initiated in the 1960s in the two northernmost provinces of Finland to study risk factors involved in pre-term birth and intrauterine growth retardation, and the consequences of these early adverse events on subsequent morbidity and mortality. The uniqueness of NBFCs is that the data of the cohorts were obtained from early fetal life (including maternal health during pregnancy) to adulthood. The NFBC1966 includes 12,058 live births to mothers in the two northern-most provinces of Finland. Two decades later, a second cohort of 9432 births was obtained (NFBC1986). In NFBC1966 pregnancies were followed prospectively from the first antenatal contact (10-16th week). After birth, the offspring were examined and then again underwent clinical evaluation at ages 1y, 7y, 14-16y and 31y. At each visit, a wide range of phenotypic, lifestyle and demographic data were gathered by questionnaires and clinical examinations. For the most part, NFBC1986 has undergone similar evaluations to NFBC1966. Linkage to national registries includes hospitalization, deaths, education, medication, pensions, and provides up-to-date demographic and clinical information for members of both cohorts. DNA samples were obtained from 5,923 subjects from NFBC1966 and 6688 subjects from NFBC1986. Data coverage, 96% of all births in 1966 and 99% in 1986, is highly representative for the whole population. The NFBC program comprises more than 20 different projects coordinated by the Center of Lifecourse Disease studies in Northern Finland (COLD) at Oulu University. The prospective data collected from the NFBCs form a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioral risk factors. The genome-wide association (GWA) study sponsored through the STAMPEED program of NHLBI employed genomic DNA samples previously collected by the NFBC1966 study and stored in the DNA repository of the National Institute for Health and Welfare, Finland. This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to metabolic and cardiovascular diseases (CVD). In addition to de-identified genome wide genotypic data, a selected list of phenotypic data related to CVD including weight, height, BMI, HDL, LDL, total cholesterol, triglyceride, glucose, insulin and fasting status, are also available in dbGaP. A summary of the GWAS for the NFBC1966 cardiovascular risk traits can be found in Sabatti et al., Nature Genetics 41: 35-46, 2009, PMID: 19060910. The version 2 release of this study contains sequence data from seventeen loci associated with levels of triglyceride, HDL-C, LDL-C, total cholesterol, fasting plasma glucose, and fasting plasma insulin (Kathiresan et al. 2008, Willer et al. 2008, Sabatti et al. 2009, Dupuis et al. 2010, Teslovich et al. 2010). At each locus, protein-coding regions and 5' and 3' untranslated regions of genes nearest to single nucleotide polymorphisms showing genome-wide significant association with metabolic syndrome-related traits, were sequenced. Targeted Illumina sequencing of 78 genes (~270kb) using 150bp probes was performed on 4943 subjects of the Northern Finland Birth Cohort 1966 (NFBC1966). Whole exome sequencing on the Illumina platform was carried out on 586 of those participants. The sequencing study is part of a larger project that is funded by the National Human Genome Research Institute's Allelic Spectrum in Common Disease Initiative, and comprises sequence data from more than 7000 individuals in two Finnish cohorts: NFBC1966 and the Finland-United States Investigation of NIDDM Genetics (FUSION) study.

Study phs000276

ALCHEMIST Study

The ALCHEMIST study will accrue patients that are potentially eligible for the Intergroup adjuvant studies and perform central EGFR and ALK genotyping using a central reference laboratory certified by the Clinical Laboratory Improvement Amendments of 1988 (CLIA). Patients may either present prior to surgery with resectable NSCLC, may present following complete resection (before or after adjuvant chemotherapy). Eligibility is limited to those with NSCLC of a non-squamous histological subtype and those with adequate performance status and organ function for future trial eligibility. All subjects must submit tissue for central EGFR and ALK genotyping, as well as additional tissue for advanced genomics at the CCG. Subjects may have had local genotyping done prior to registration, however if these results shows no targetable EGFR or ALK alterations (or if it shows a KRAS mutation) then the patient will not be eligible for this screening protocol given the primary aim is to facilitate accrual to the adjuvant studies. All subjects will provide peripheral blood for matched normal DNA. All subjects (including those known to have EGFR or ALK alterations with local genotyping) will have formalin-fixed tissue collected for central genotyping. The testing will be performed at Response Genetics (Los Angeles, CA), a commercial CLIA-certified laboratory. ALK FISH will be performed using the Vysis break-apart probe and EGFR sequencing will be performed of exons 18-21. It is preferred that a full tumor block be submitted, but if unavailable, 15 unstained slides can be submitted. Genotyping results are expected to be provided to the treating clinician within 14 business days of submission so they can be used to determine eligibility for the randomized adjuvant studies, or to confirm the local results. Results will also be reported at intervals to the study team for update into the Alliance database. In addition to the commercial genotyping at Response Genetics, tissue will be collected for research genomics by CCG. For those patients with a block available, this will be forwarded to the CCG after clinical testing at Response Genetics. For patients without a block available, 15 unstained slides should be submitted to the CCG BCR for exploratory analysis. A peripheral blood specimen will also be collected and sent to the CCG BCR to use as matched normal. Specimens will be coded. Over the course of the study, the CCG will perform advanced genomic analysis of the resected lung cancer specimens in a research, non-CLIA environment. Following completion of the genomic analysis, the results can be matched with the clinical follow-up results using a link between the samples codes and the patient identifiers for correlative analyses. Subjects participating in the follow-up portion of the ALCHEMIST study, as well as those participating in the adjuvant therapeutic studies, are expected to undergo a standard-of-care diagnostic biopsy to confirm recurrence. At least two core biopsies, minimum, should be obtained as part of this recurrence biopsy. Paraffin embedded tissue from this biopsy will be used for confirmation of recurrence, for CLIA genomics to plan subsequent clinical trials, and for additional research genomics by the CCG. Plasma will additionally be collected at recurrence and sent to CCG for study of circulating free DNA (cfDNA). Data for the ALCHEMIST study is not yet available to be accessed by the public at this time; when ready it will be made available at the GDC Data Portal.

Study phs001140

Genome-Wide Analysis of Diffuse Large B-Cell Lymphoma (De Novo and Derived from the High Grade Transformation of Follicular Lymphoma)

Version 1. Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). The molecular pathogenesis of DLBCL is associated with multiple genetic lesions that in part distinctly segregate with individual phenotypic subtypes, suggesting the involvement of distinct oncogenic pathways. However, the lesions identified so far likely represent only a fraction of those necessary for malignant transformation. In order to characterize the entire set of structural alterations present in the DLBCL genome, we have integrated next generation whole exome sequencing analysis of 6 DLBCL cases and genome-wide high-density SNP array analysis of 72 DLBCL cases. We report here that FL and DLBCL harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~37% of DLBCL and 36% of FL cases display genomic deletions and/or somatic point mutations that remove or inactivate the HAT coding domain of these two genes. These lesions commonly affect a single allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in the acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumor suppressor. These results identify CREBBP/EP300 mutations as a major pathogenic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. Version 2. Follicular lymphoma (FL) is an indolent, but incurable disease that, in 30-40% of cases, undergoes transformation to an aggressive diffuse large B cell lymphoma (DLBCL). The history of clonal evolution and the mechanisms that underlie transformation to DLBCL (tFL) remain largely unknown. Using whole exome sequencing and copy number analysis of 39 tFL patients, including 12 with paired sequential FL/tFL biopsies, we show that, in most cases, FL and tFL arise by divergent evolution from a common mutated precursor cell through the acquisition of distinct genetic lesions. Mutations in epigenetic modifiers (e.g., MLL2, CREBBP, EZH2, ARID1A) and anti-apoptotic genes (BCL2, FAS) were observed in 93% (36/39) and 78% (30/39) of cases, respectively, and were invariably shared between the two disease phases, suggesting an early acquisition in the common mutated precursor. Conversely, the development of tFL is associated with deregulation of genes involved in the control of cell proliferation, cell cycle progression and DNA damage responses (CDKN2A/2B, MYC, TP53), as well as with an aberrant activity of the somatic hypermutation mechanism. Finally, we show that the genomic profile of tFL shares significant similarities with that of germinal center B-cell type de novo DLBCL, but also displays unique combinations of altered genes that may explain the dismal clinical course of tFL.Version 3. This version includes thirty-five additional de novo DLBCL samples, newly diagnosed, and their paired normal DNA from previously untreated patients, which were analyzed by whole exome sequencing (n=27T and 25N), whole genome sequencing (8T and 10N), and/or targeted HLA-next generation sequencing (n=26T/N pairs) in order to identify genetic alterations associated with loss of surface MHC-II expression.

Study phs000328

Integration of Clinical and Molecular Biomarkers for Melanoma Survival (Berwick)

The long-term goal of the InterMEL Program Project: Integration of Clinical and Molecular Biomarkers for Melanoma Survival is to identify molecular and clinical factors that predict survival of melanoma patients. Our overarching hypothesis is that we can identify factors in the primary melanoma tumor that will lead to more aggressive disease. Melanoma patients diagnosed at American Joint Committee on Cancer (AJCC) tumor, lymph nodes, and metastases (TNM) stages IIA/IIB/IIC/IIIA/IIIB/IIIC/IIID display highly variable clinical outcomes and responses to therapy. We wish to identify robust and reproducible biomarkers or sets of classifiers that distinguish patients likely to have poor prognosis. These biomarkers will help establish targets for adjuvant therapies for this set of patients before the tumors metastasize. Aim 1. Classify actionable somatic mutations, and copy number variations (CNVs) in relationship to melanoma survival. In Project 1, Targeted Sequencing and Clinicopathology to Evaluate Primary Melanoma Molecular Subtypes and Outcomes, we will profile 468 genes using the MSKIMPACT ™ assay and identify somatic mutations and CNVs associated with melanoma-specific survival, as well as their co-occurrence with other mutations, in 1,000 tumors from patients at AJCC TNM stages IIA-IIID: approximately 500 from patients who died with melanoma within five years and approximately 500 from individuals who have lived at least five years. We will also evaluate the joint effects of somatic mutations, CNVs and pathologic characteristics associated with good and poor outcomes. Aim 2. Identify primary melanoma DNA methylation profiles to evaluate subtypes and survival. Although it has been established that melanomas frequently have aberrant DNA methylation, it is unknown if DNA methylation in primary melanomas predicts outcome. In Project 2, Primary Melanoma DNA Methylation Profiling for Evaluating Subtypes and Survival, we will profile the same primary melanomas as in Project 1 with Illumina Infinium 850K methylation arrays. We expect to: identify and characterize DNA methylation-based melanoma subclasses; train, test and validate a CpG signature prognostic for survival from melanoma; determine whether this profile adds information to outcome prediction beyond AJCC TNM staging. This project is based on the hypothesis that DNA methylation in primary melanoma will define subgroups (including a poor-prognosis CIMP – ‘CpG island methylator phenotype' subtype) and that a CpG signature will be prognostic for melanoma survival. Aim 3. Define microRNA expression changes in relation to melanoma survival. MicroRNAs have been associated with poor prognosis in melanoma, as well as in other cancers. In Project 3, Prognostic and Functional Role of a Gene Expression Signature in Melanoma Patients, we hypothesize that altered miRNA expression, captured at the time of diagnosis, may contribute to the aggressive behavior of a subset of early stage primary melanomas. We will profile the same primary melanomas as in Projects 1 and 2 with a Nanostring assay. This project will define and validate a tissue-based microRNA signature in conducted to determine whether the prognostic miRNA signature, as well as other candidate genes emerging from other projects, contribute to melanoma survival. Aim 4. Integrate data from multiple platforms to identify melanoma subtypes and survival. Despite substantial literature on gene tumor mutation-, methylation- and gene expression-based prognostic and predictive signatures for melanoma, few such signatures are used in clinical practice. Project 4, Multiplatform Analysis of Melanoma Molecular Subtypes and Patient Survival Outcome, will use novel integrative clustering methods to identify molecular subtypes of melanoma jointly defined across these platforms.

Study phs003099

Acute Respiratory Distress Network (ARDSNet) Studies 01 and 03 Lower Versus Higher Tidal Volume, Ketoconazole Treatment and Lisofylline Treatment (ARMA/KARMA/LARMA) (ARDSNet-ARMA/KARMA/LARMA-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ARMA/KARMA/LARMA include plasma, serum and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. Background Participants suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in participants with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response. Participants The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 participants in each trial. A total of 860 participants were randomized into the ventilator management trial. Participants enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo. Conclusions Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for participants with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (PMIDs: 10789668, 11902249, 10793162).

Study phs003734

ARDSNet 07-08: Randomized, Blinded, Placebo-Controlled, Multi-Center Trial of Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidants in Acute Lung Injury or ARDS (OMEGA) (ARDSNet-Omega-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-Omega include bronchial lavage, plasma, urine, and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine if dietary supplementation of omega-3 (n-3) fatty acids, γ-linolenic acid and antioxidants to participants with acute lung injury would increase ventilator-free days to study day 28.Background: Early acute lung injury (ALI) is characterized by neutrophilic lung inflammation, permeability, and intravascular and alveolar fibrin deposition. The type and inflammatory activity of eicosanoids liberated during inflammation depends on the membrane phospholipid composition: omega 6 (n-6) fatty acid arachidonate yields highly reactive and inflammatory dienoic prostaglandins and series 4 leukotrienes, whereas omega-3 (n-3) fatty acids favor production of less active and potentially anti-inflammatory trienoic prostaglandins and series 5 leukotrienes. Participants at risk of developing ALI have n-3 levels approximately 25% of normal and those with established ALI have n-3 levels as low as 6% of normal, suggesting a potential role for n-3 dietary supplementation in participants with ALI.Three randomized controlled studies, conducted in participants with ALI or sepsis-induced respiratory failure, demonstrated an association between the administration of an enteral formula enriched in n-3 fatty acids, GLA, and antioxidants and improved oxygenation and respiratory physiology compared with an unenriched, high-fat formula. However, interpretation of these results is limited by the small sample sizes and as-treated analyses of only those participants who tolerated full enteral nutrition. Participants: The total number of participants in the study was 272.Design: Participants were stratified by hospital and the presence of shock at baseline and then randomized to receive either twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants (n-3 supplement) or an isocaloric-isovolemic carbohydrate-rich control. Participants were also simultaneously randomized to a separate ongoing trial (the EDEN study) comparing low- vs full-calorie enteral nutrition in a 2×2 factorial design.The n-3 or control supplement was administered enterally as twice-daily boluses of 120 mL beginning within 6 hours of randomization. Dosing continued until the earliest of 21 days, 48 hours of unassisted breathing, or extubation. The energy provided by the boluses supplemented that provided by each primary physician's choice of standard continuous non–n-3-enriched enteral formula. The rate of continuous enteral feeding was managed by a protocol with an algorithm for gastrointestinal intolerances. The supplement was administered even if enteral nutrition was interrupted, as long as the patient was tolerating enteral medications. Conclusions: The study was stopped by the DSMB for futility at the first interim analysis after 143 participants had been randomized to receive the n-3 supplement and 129 to receive the isocaloric control. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, participants receiving the n-3 supplement had fewer ventilator-free days, intensive care unit–free days, and nonpulmonary organ failure-free days.

Study phs003744

Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation on Helicopter Study (PROHS) (ROC-PROHS-BioLINCC)

Accessing Data: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Objective: To observe if patients with severe traumatic injuries evacuated to level 1 trauma centers on air ambulances who received prehospital red blood cells and/or plasma had decreased in-hospital mortality compared to patients who received only crystalloids.Background: Injury is the leading cause of death in adults and children between the ages of 1 and 44 years. However, approximately 40% of in-hospital deaths among injured patients involve massive truncal hemorrhage that is considered potentially salvageable. Multiple retrospective military and civilian studies have reported that transfusion involving blood component ratios approaching whole blood are associated with significant decreases in 24-hour and 30-day mortality among injured patients. Furthermore, prehospital transfusion (PHT) studies from military and civilian hospitals have shown that prehospital transfusion of plasma and red blood cells (RBCs) is not only feasible, but associated with improved coagulation status on arrival. Prehospital resuscitation practices in the US differ significantly in approach, with most systems using crystalloids while a few offer RBCs or a combination of plasma and RBCs. No large multicenter civilian studies have evaluated the use of prehospital plasma and RBCs in severely injured patients compared to crystalloids.Participants: A total of 25,118 trauma patients were admitted during the 10 month enrollment period to the nine participating centers, of which 2341 arrived by helicopter, and 1058 met the highest risk criteria. Of the high risk sub-set, 585 arrived on helicopters with blood products available and 473 patients arrived via helicopters without blood available. One hundred forty two patients (24%) of those transported on helicopters with blood products available actually received PHT and 916 patients did not.Design: PROHS was a multicenter, prospective pragmatic, observational study of prehospital resuscitation approaches. There were no study guidelines dictating resuscitation practice (i.e., use of blood products or end of resuscitation). Of the 9 participating Level I trauma centers, 5 had helicopter systems with plasma and/or RBCs while the other 4 had helicopter systems that used only crystalloid resuscitation. All patients arriving to the participating center's trauma emergency department via helicopter directly from the scene were screened and had initial data collected. Of that group, all patients who met the highest risk category or received blood during transport were followed by direct observation during the initial resuscitation period and then indirectly through medical chart review until hospital discharge or 30 days after admission (whichever occurred first).The primary outcome was in-hospital mortality at 3 hours, 24 hours, and 30 days. Other outcome measures included length of hospital stay, number of ICU days, number of ventilator days, blood product usage, GOSE score at discharge, number of patients with complications, and number of patients who required hemostatic devices. Conclusions:Because of the unexpected imbalance in injury severity between systems with and without blood products on helicopters, all analyses were inconclusive. With few units transfused to each patient and small outcome differences between groups, large randomized studies will be required to detect significant survival differences in this important population.

Study phs003826

Prediction of Resistance and Sensitivity to HER2 Targeted Therapy in the Neoadjuvant Setting

Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential adriamycin and cyclophosphamide (AC) followed by weekly paclitaxel neoadjuvant regimen. Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues. This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.Tumor samples were collected prior to and post-treatment, and RNA sequencing was performed with this version.

Study phs003275

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