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• shallow WGS and deep targeted panel on ctDNA in rhabdomyosarcomas

  The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this study we investigate 35 patients with relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS). Targeted DNA or whole exome sequencing (WES) was used to detect alterations in paired primary/relapsed samples. In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted custom RMS panel (36 genes) at high coverage for single nucleotide variation and fusion detection, and a shallow whole genome sequencing for copy number variation. FP-RMS had a stable genome with relapse, with the most common secondary alterations : CDKN2A/B, MYCN and CDK4 alterations, being already present at diagnosis and impacting overall survival. FP-RMS lacking major secondary events at baseline acquired recurrent MYCN and AKT1 alterations. FN-RMS acquired a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detected pathognomonic variants in all RMS patients at diagnosis, regardless of FP/FN or type of alterations, while at relapse selected alterations were confirmed in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads was detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression within a relatively stable genomic landscape and provide rationale for using liquid biopsy to monitor treatment response.

  Study EGAS00001007399

• OMKar

  The whole genome karyotype refers to the sequence of large chromosomal segments that make up an individuals genotype. karyotype analysis, which includes descriptions of aneuploidies and other rearrangements is crucial for understanding genetic risk factors, for diagnosis, treatment decisions, and genetic counseling linked to constitutional disorders. The current karyotyping standard is based on microscopic examination of chromosomes, a complex process that requires high expertise and offers Mb scale resolution. Optical Genome Mapping (OGM) technology can identify large DNA lesions in a cost-effective manner. In this paper, we developed OMKar, a method that uses OGM data to create a virtual karyotype. OMKar processes Structural (SV) and Copy Number (CN) Variants as inputs and encodes them into a compact breakpoint graph. It recomputes copy numbers using Integer Linear Programming to maintain CN balance and then identifies constrained Eulerian paths representing entire donor chromosomes. In tests using 38 whole genome simulations of constitutional disorders, OMKar reconstructed the karyotype with 88% precision and 95% recall on SV concordance and 95% Jaccard score on CN concordance. We applied OMKar to 50 prenatal, 41 postnatal, and 63 parental samples from ten different sites. OMKar reconstructed the correct karyotype in 144 out of 154 samples, covering 25 of 25 aneuploidies, 32 of 32 balanced translocations, and 72 of 82 unbalanced variations. Detected constitutional disorders included Cri-du-chat, Wolf-Hirschhorn, Prader-Willi deletions, Down, and Turner syndromes. Importantly, it identified a plausible genetic mechanism for five cases of constitutional disorder that were not detected by other technologies. Together, these results demonstrate the robustness of OMKar for OGM-based karyotyping.

  Study EGAS00001008245

• The Institute for Genomic Medicine at Nationwide Children's Hospital Pediatric Cancer and Blood Disorder Project

  The aim of this study is to enable the unification of the clinical and research arms of comprehensive genomic profiling in the setting of cancer and hematologic disease. Increasingly, studies of the genomic etiology of cancer and hematologic diseases are being utilized for patient management, including prognostication, informing diagnosis, and evaluating eligibility for targeted therapeutics and clinical trials. Clinically available testing can be limited in scope and follow-up, and thus assessment of the impact on patient outcomes is difficult to ascertain. N-of-1 studies have the ability to more broadly impact our understanding of the mechanisms of cancer and hematologic disease, and can have benefit for the individual as well as the larger population of patients with these diseases. Thus, we seek to study and characterize the genomic underpinnings of cancer and hematologic disease through genomic profiling studies bridging both clinical and research components. We will rigorously perform and vet research sequencing and genomic studies protocols for the purpose of transitioning these assays to clinically valid testing for use in clinical patient care. We have been enrolling patients onto this comprehensive genomic profiling study since January 2018. As part of the genomic workup for these patients, we have been performing tumor and normal whole genome sequencing, whole exome sequencing and RNA-Seq. The project is largely supported by the Nationwide Children's Foundation, and we anticipate adding another 50-70 cases per year. This protocol is significant in that it expands our understanding of the etiology of cancer and hematologic disease through a comprehensive analysis aimed at detecting a broad scope of genomic aberrations. Additionally, it improves our understanding of the clinical utility of genomic profiling and has the potential to ultimately improve patient management and surveillance at both level of an individual and general populations of patients affected by these diseases. Primary Objectives: Aim 1: Use diagnostic, relapse, and/or germline samples for augmented whole exome sequencing to characterize the spectrum of germline and somatic genomic alterations in pediatric malignancies and hematologic disease. Aim 2: Examine gene expression and fusion events using whole RNA-seq "transcriptome" analysis or targeted RNA-seq analysis such as the Archer FusionPlex technology. Aim 3: Compare the results of our enhanced molecular profiling vs. that which is detectable by traditional methods as related to cytogenetic, molecular, and minimal residual disease analyses performed as part of standard of care. Aim 4: Examine the utility of comprehensive genomic profiling by collection and evaluation of outcomes data as related to enhancement/alteration in diagnosis, prognosis, treatment management, and clinical benefit. Secondary Objective: Aim 1: Use and clinically validate expanded laboratory methodologies and bioinformatic approaches to more broadly assess genomic complexity (e.g. whole genome sequencing, transcriptome sequencing, in vitro analyses, minimal residual disease testing, clonality assays, proteomics) in the setting of hematologic and oncologic disease. In so doing, we aspire to make novel discoveries and associations, as related to disease phenotypes and subtypes, variant causality, therapeutic targeting, and cancer biology.

  Study phs001820

• Whole-Genome Sequencing in Multiplex Epilepsy Families

  Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies. The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases. Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  Study phs000690

• RNA-Sequencing of cervical cancers

  Question: Can we identify cervical cancer patients who are at risk for distant metastatic (DM) recurrence following treatment with radiotherapy, concurrent weekly cisplatin and brachytherapy (RTCT). Findings: An immune-based 55 gene risk score was developed using a cohort of 81 patients treated with RTCT that was strongly predictive of DM and cause-specific survival (CSS). The risk score was validated in two independent patient cohorts. A high immune metastatic risk score was associated with a high tumor mutational burden and a ‘cold’, immune-excluded tumor microenvironment at diagnosis. Meaning: The immune gene expression risk score may help to identify patients at risk of DM and potential targets for mitigating this risk.

  Study EGAS50000000087

• Epigenomics Studies in Acute Myeloid Leukemia (AML)

  Acute Myeloid Leukemia (AML) remains a clinical challenge since most patients diagnosed with AML will die from the disease. Some patients harbor treatment-refractory disease and many others relapse with disease that in many cases is resistant to treatments. Our study was designed to understand the molecular basis of disease progression in AML through assessing genomics signatures in patient specimens collected through an international collaboration which assembled samples from 138 AML patients which experienced disease relapse and normal hematopoietic cells (n=15). It is hoped that this resource will help researchers understand mechanisms of disease relapse in AML and contribute to the general pool of data available for analyses for this disease and general research use.

  Study phs001027

• Selenium Chemoprevention: Benefits and Harms

  Selenium is a trace element that may have anti-carcinogenetic effect, but heterogenous treatment effects have been observed. This genome-wide association study investigates if genetic variation modifies the effect of selenium chemoprevention in the Selenium and Celecoxib Trial, a randomized, double-blind, placebo-controlled trial conducted at the University of Arizona Cancer Center. The objective of the clinical trial was to determine whether daily intake of 200 µg/d of selenium as a supplement could reduce the risk for developing metachronous colorectal adenomas. The study participants were recruited between 2001 and 2011. Genome-wide association study was performed for 1,323 study participants who provided blood sample at the time of study entry.

  Study phs002283

• Enhancer Mapping in Chronic Lymphocytic Leukemia

  In this study we profile the epigenomic enhancer landscapes of CLL B cells (CD19+/CD5+) harvested from peripheral blood of patients from our Center. Included are results of ChIPseq profiling using chromatin immunoprecipitation of the enhancer histone mark H3K27ac (acetylated lysine 27 on histone H3), and open chromatin profiles using ATAC-seq (assay for transposase accessible chromatin). These profiles are used to define the global enhancer and super enhancer landscape of CLL B cells, and to derive active transcription factor networks associated with this disease. Also included are H3K27ac ChIP-seq and ATAC-seq datasets for non-CLL B cells obtained from the peripheral blood of normal adult donors.

  Study phs001704

• The Genomic Analysis of Medulloblastoma

  Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.

  Study phs000409

• Genomic Psychiatry Cohort (GPC) Whole Genome Sequencing and Genotyping Study

  The Center for Genomic Psychiatry at the University of Southern California (USC), SUNY Downstate and an extensive network of academic medical centers have created the Genomic Psychiatry Cohort (GPC). The GPC consists of a large clinical cohort of patients with schizophrenia, bipolar disorder, and healthy controls. The data generation of genotyping and whole genome sequencing of the GPC has been done in collaboration with the USC and the Broad Institute of MIT and Harvard. Genome-wide association studies are being performed with the samples to identify genetic risks for psychiatric disease. Genotyping is also being used to determine ancestry informative markers and replication of candidate genes. Whole genome sequencing identifies functional variants associated with disease risk.

  Study phs001020

• Genomic Landscape of High-Grade Neuroendocrine Neoplasms

  This project is a multi-omics study of high grade (grade 3) neuroendocrine neoplasms across diverse organs. Genomic analysis using low-pass whole genome sequencing for copy number analysis, whole exome sequencing and whole transcriptomic sequencing using RNAseq were performed. As high grade neuroendocrine neoplasms are highly lethal with a median survival of approximately 7 months, new insights are urgently needed for better prognosis, diagnosis and management. This study focuses on gene and pathway discoveries in this cancer, and includes samples from a diverse set of organs, including the lungs, gastroenteropancreatic tract, breast, prostate, head and neck and bladder. This study was made possible by a generous donation from The Helen B. Rodde Fund.

  Study phs002070

• CADD/GADD centers on Antisocial Drug Dependence

  CADD (Center for Antisocial Drug Dependence): Funded through NIDA 011015 to study genetic influences on, and treatment of, antisocial drug dependence, studying both clinical probands and their families, and community samples of matched controls, twins, and participants in an ongoing longitudinal adoption study. A collaboration between three organizations at two campuses of the University of Colorado. Longitudinal with three waves of data collection completed. GADD (Genetics of Adolescent Antisocial Drug Dependence): Funded originally through NIDA 012845, s multisite collaboration including adolescent subjects at high-risk for antisocial drug dependence and their siblings, recruited in Denver, CO and San Diego, CA. Longitudinal with two waves of data collection completed, one in progress as of May, 2018.

  Study phs001841

• Sequence Analysis of Mutations and Translocations Across Breast Cancer Subtypes

  This study combined whole exome (103 samples) and whole genome (22 samples) sequencing over a total of 108 breast tumors and matched normal DNA to identify novel mutations and translocations. Samples were subjected to paired-end Illumina sequencing with goal of 30x coverage of tumor/normal for whole genomes and 100x tumor/normal coverage for whole exomes. From these sequences, we used various computational techniques to identify somatic point mutations, insertion/deletions and structural rearrangements in these tumors. From these data, we identified new insights into the rates of background mutations in these cancers, novel recurrent mutated genes, and multiple gene rearrangements. One of these rearrangements appears to be a recurrent event in breast cancer.

  Study phs000369

• Epilepsy Genetics Initiative

  The Epilepsy Genetics Initiative (EGI) was created in 2014 with the goal of amassing a database of clinically-generated exome sequence data for patients with epilepsy who have had diagnostic whole exome sequencing. Most of the subjects enrolled in the study did not receive a secure genetic diagnosis from their initial sequencing. Following participant/family consent, EGI transfers raw data from the respective clinical lab to the Institute for Genomic Medicine at Columbia University Medical Center. The strategy of the initiative has been to carry out systematic reanalysis of data to identify new diagnoses that were not possible or missed at the time of initial sequencing and to aid in novel gene discovery in epilepsy.

  Study phs001551

• Improved Detection and Identification of Microsatellite Instability Features in Colorectal Cancer

  In this study, we analyzed a series of colorectal cancers using a new sequencing technology that sequences more than 200 microsatellite regions in parallel. With this technology, we evaluated mono-, di- , tri- and tetranucleotide repeats to provide a broad spectrum of microsatellite instability (MSI) events. This deep sequencing technology provides greater than 2000X coverage and eliminates the need for PCR amplification. Because every read corresponds to a single DNA molecule, we eliminated artifacts introduced by PCR that obscured true MSI events. Also included in our analysis is a new method for detection of somatic copy number changes in 83 cancer genes, with which we can infer chromosomal instability (CIN) status.

  Study phs001914

• Mega-GWAS ALS I

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder clinically characterized by rapidly progressive paralysis and death due to respiratory failure, typically within two to three years of symptom onset. The number of ALS cases across the globe will increase to nearly 400,000 in 2040, predominantly due to aging of the population. Unraveling the genetics underlying ALS provides insights into the cellular mechanism leading to motor neuron death and provides targets for therapeutic intervention. We performed a genome-wide association study involving a meta-analysis of 20,806 ALS cases and 59,804 controls. The current study release makes available genotype data of the 15,480 subjects assayed in the Laboratory of Neurogenetics for this effort.

  Study phs000101

• Cutaneous Melanoma GWAS Combining Multiple Populations and Risk Phenotypes

  Most genetic susceptibility to cutaneous melanoma (CM) remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with nevus count and hair colour GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 CM susceptibility loci. These findings provide substantial insights into CM genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for CM pathogenesis.

  Study phs001868

• NHLBI TOPMed - NHGRI CCDG: UCSF Atrial Fibrillation Study

  The University of California San Francisco (UCSF) Cardiovascular Research Institute (CVRI) Resource in Arteriosclerosis and Metabolic Disease is an ongoing multi-ethnic study of adults ≥ 18 years of age which was started in 1989 and now includes 28,000 participants recruited from the UCSF medical system. Within the Resource lies data and biospecimens from nearly 1,000 patients presenting to the electrophysiology laboratory for electrophysiology procedures that were densely phenotyped for electrophysiologic characteristics with biospecimens collected from various intra and extra-cardiac chambers. Phenotyping of all participants was achieved via interview and review of medical records. A subset of 113 participants with early-onset atrial fibrillation underwent WGS as a part of the TOPMed Program.

  Study phs001933

• Phylogenetic Analyses of Melanoma Reveal Complex Patterns of Metastatic Dissemination

  Subpopulations of cells in a primary melanoma can disseminate and establish metastases. Still, the precise ancestral relationship between primary tumors and their metastases is not well understood. Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of 8 patients to determine their phylogenetic relationships, profiling a total of 31 total tumors. The resulting data show that in 6 of 8 cases, genetically unique cell populations in the primary metastasized in parallel to distinct anatomic sites, rather than sequentially. These data also indicate that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct.

  Study phs000941

• Cryptic Splice Mutation in the Fumarate Hydratase Gene in Patients With Clinical Manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

  Four patients with hysterectomy were evaluated for biochemical and molecular evidence of autosomal dominant Fumarate Hydratase (FH) alterations causing Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). HLRCC is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas, and risk for development of an aggressive form of papillary renal cell cancer. Enzyme assay, western blot analyses, direct nanopore RNA sequencing, and whole genome sequencing (WGS) were utilized. The study identified a cryptic splice mutation in intron 9 of the FH gene that results in retention of 57 base pairs of intronic sequence in the affected allele of the mature FH mRNA.

  Study phs003381

• Single-cell RNA sequencing of pediatric Hodgkin Lymphoma to study the inhibition of T cell subtypes

  Here, we applied single-cell RNA-sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. This allowed us to identify genes of cell surface proteins that are consistently overexpressed in HRS cells and can potentially be used as targets for antibody-drug conjugates or CAR T cells. Finally, we identify potential interactions by which HRS cells inhibit T cells, among which the Galectin-1/CD69 and HLA-DRA/LAG3 interactions. However, high levels of inter-patient heterogeneity of the interaction strength were observed. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets.

  Study EGAS50000000432

• ROBUST (NCT02285062)

  The ROBUST clinical trial is a Phase III, randomized, double-blind, placebo-controlled study designed to compare the efficacy and safety of lenalidomide plus R-CHOP chemotherapy (R2-CHOP) versus placebo plus R-CHOP in newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Molecular data was collected for all patients at screening, but the only patients of the Activated B-cell (ABC) cell-of-origin subtype were eligible for study inclusion and clinical follow-up. We have performed unsupervised clustering on this cohort and identified 7 novel transcriptional subtypes of DLBCL, one of which represents a high-risk subset of patients with high MYC expression, ABC-associated biology, and low immune infiltration.

  Study EGAS50000000333

• Genomics of Acute Myeloid Leukemia

  Sequence data from the Genomics of AML PPG program at Washington University since 2009 is made available. This repository contains data from tumors (bone marrow or peripheral blood) from Acute Myeloid Leukemia (AML) and several other related disorders - myelodysplastic syndromes (MDS), secondary AML (sAML) and therapy-related AML (tAML). It also contains matched normal data (skin or buccal swab) and healthy donors for comparison. A variety of DNA sequencing assays were used, including whole genome sequencing (WGS), exome sequencing, targeted panels of AML genes, or targeted panels for validation. Other modalities, including RNA-seq, small RNA-seq, whole genome bisulfite sequencing, CHIP-seq, ATAC-seq, and single-cell RNAseq are also represented.

  Study phs000159

• Precision Diagnosis of Neurodevelopmental Disorders in Middle Eastern Populations

  We constructed de novo genome assemblies for six family trios from diverse Middle Eastern ancestries (Sudan, Jordan, Syria, Qatar, and Afghanistan), involving probands with various unresolved neurodevelopmental conditions. We generated high-quality, nearly complete genome assemblies for trios, revealing extended novel sequence impacting known genes, novel HLA/KIR alleles, and strong signals of inbreeding, with runs of homozygosity covering large parts of individual chromosomes. We also identified potential disease variants underlying the unresolved symptoms. Also, the assemblies uncovered unique variation relative to existing references, showing enhanced mapping and variant calling of Middle Eastern genomes. The dataset available through dbGaP includes raw short (Illumina) and long (PacBio) sequencing reads and assembled haplotypes.

  Study phs003917

• CpG methylation changes associated with hyperglycemia in type 1 diabetes occur at angiogenic glomerular and retinal gene loci.

  Retinal and glomerular microangiopathy, and cardiovascular disease, contribute to the morbidity and mortality observed in adults with type 1 diabetes (T1D). While the level and duration of hyperglycemia are primary factors influencing these complications, the underlying molecular mechanisms behind glucose-induced organ damage remain poorly understood. In this study, blood samples from young T1D patients at diagnosis and three years later in average were analyzed for DNA methylation using whole-genome bisulfite sequencing. Significant DNA methylation changes in critical angiogenic gene loci were associated with HbA1c, a direct hallmark of chronic hyperglycemia. This finding may offer novel epigenetic insights for a better understanding of T1D complications.

  Study EGAS50000000370