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• DAXX restoration suppresses alternative lengthening of telomeres in ATRX wild-type cells

  Many tumors maintain chromosome ends through a telomerase-independent, homologous recombination based mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes encoding components of the histone H3.3 chaperone complex, ATRX and DAXX. To date the mechanistic role of ATRX and particularly DAXX mutations in potentiating ALT remains poorly understood. We identify an osteosarcoma cell line, G292, with a unique chromosomal translocation resulting in loss of DAXX function, while retaining functional ATRX. Using this distinctive resource, we demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores localization of the ATRX/DAXX complex to PML bodies. This provides the first direct molecular evidence that ongoing DAXX deficiency is essential for maintenance of the ALT phenotype and highlights the potential for therapeutic targeting of this oncogenic pathway.

  Study phs001495

• The Two Sister Study: A Family-Based Study of Genes and Environment in Young-Onset Breast Cancer

  To study environmental and genetic causes of young onset breast cancer, we recruited women who had been young when recently diagnosed (under age 50 and within 4 years of enrollment), and had been identified as potentially eligible by a sister who was already participating in the ongoing Sister Study. The unaffected sister had already provided consent, questionnaire-based information and DNA (blood-based) when she enrolled in the Sister Study. Her case sister then provided comparable questionnaire-based information and DNA via a mail-back saliva collection kit. To enable family-based analyses, parents were also asked to (only) provide consent and a saliva sample. Because the cases were young-onset, most parents were alive, but unavailability of the parents was not a basis for exclusion. The study was funded in part by Susan G. Komen for the Cure.

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• Identification of 22 Novel Loci Associated with Susceptibility to Testicular Germ Cell Tumors

  Testicular germ cell tumors (TGCT) are the most common cancers in young men of European ancestry aged 20 to 39 years. The Testicular Cancer Consortium (TECAC) has brought together the largest genome-wise association study (GWAS) study of TGCT to date. We conducted a GWAS of 5,602 cases and 5,006 controls aggregated from 12 locations in the US and Europe. Logistic regression models adjusted for study center and genomic ancestry. Genotypes were imputed against the Human Haplotype Reference Consortium. Meta-analysis was performed to combine GWAS results with summary statistics from five previously published TGCT studies, UK Biobank, deCODE Genetics, and an independent set of cases and controls, for a total of 10,156 cases and 179,683 controls. 22 novel and 45 previously reported loci associated with TGCT surpassed genome-wide significance (p < 5e-08).

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• National Heart, Lung, and Blood Institute SNP Health Association Asthma Resource Project (SHARP)

  SNP Health Association Resource (SHARe) Asthma Resource project (SHARP) is conducting a genome-wide analysis in adults and children who have participated in National Heart, Lung, and Blood Institute's clinical research trials on asthma. This includes 1041 children with asthma who participated in the Childhood Asthma Management Program (CAMP), 994 children who participated in one or five clinical trials conducted by the Childhood Asthma Research and Education (CARE) network, and 701 adults who participated in one of six clinical trials conducted by the Asthma Clinical Research Network (ACRN). There are three study types. The longitudinal clinical trials can be subsetted for population-based and/or case-control analyses. Each of the childhood asthma studies has a majority of children participating as part of a parent-child trio. The ACRN (adult) studies are probands alone. Control genotypes will be provided for case-control analyses.

  Study phs000166

• Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

  This study of DNA and RNA sequencing of 5 parent-offspring trios is a single center study. The goal of this study is to characterize X chromosome inactivation (XCI) ratio in females using phased genomic variations obtained through whole genome or exome sequencing in trios, followed by allele-specific expression analysis of the phased, heterozygous alleles in the mRNA of the female offspring, and to apply this method to clinical diagnosis. The distribution of allele ratios across X obtained from mRNA sequencing allows for the estimation of X inactivation status of inherited X chromosomes, and the parameters of each parental allele distributions in the offspring's mRNA data can be used as determinants for XCI ratio. This approach was used to evaluate the contribution of skewed XCI ratio to phenotypic heterogeneity in an undiagnosed, mild neurological condition.

  Study phs000816

• University of Texas at Austin (UTA) Histone Modification and Gene Expression Profiling in 9 Primary Glioblastoma Multiforme, 2 Anaplastic Astrocytomas and Two Meningiomas

  The primary goal of this study was to collect and analyze genomic data from primary glioblastoma multiforme tumors. Our collaborators at St David's Medical Center (SDMC) obtained informed consent from patients undergoing surgery to remove a tumor in the brain. After consent was obtained, specimens were removed from the operating suite and flash frozen in liquid nitrogen. Tumors were analyzed if they were a grade III (anaplastic astrocytoma) or grade IV glioma (glioblastoma multiforme). Tumors were transported from SDMC to UT Austin, then weighed and homogenized. Chromatin immunoprecipitation was performed for 7 proteins in each tumor (histone modifications H3K4me3, H3K4me1, H3K9ac, H3K9me3, H3K27ac, H3K27me3, and the multifunctional insulator binding protein CTCF) and no-antibody input was also sequenced. An aliquot of tumor material was set aside for isolation of total RNA.

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• Comparative Sequence Analysis Between Primary and Metastatic Colorectal Cancer Lesions

  Molecular profiling for somatic mutations that predict response to anti-EGFR therapy in colorectal cancer (CRC) has become standard practice. However, abundant tissue from metastatic lesions is not always available from patients with metastatic CRC. Concerns involving genetic heterogeneity between primary and metastatic lesions have called into question the suitability of profiling primary tumors in patients with metastatic disease. Further, the identification of discordant mutations between matched primary and metastatic tumors would be of biological interest for the delineation of biomarkers of tumor progression and metastasis. To explore the degree of genetic heterogeneity between matched primary and metastatic tumors in CRC, we performed whole genome sequencing of four patient "trios" comprised of a primary colon tumor, a liver metastasis, and matched normal (non-cancerous) tissue. Somatic mutations and indels were called in each tumor and compared between primary and metastatic lesions.

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• Genome-Wide Association Study of Relapse of Childhood Acute Lymphoblastic Leukemia

  Using risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the last 40 years. However, a substantial portion of patients experience relapse, many of whom have no known risk factors. Taking a genome-wide approach, we sought to evaluate the relationships between germline SNP genotypes and the risk of relapse in 2,535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We examine prognostic value of selected SNPs in the context of known relapse risk factors (molecular subtypes, minimal residual disease, age and leukocyte count at diagnosis). Associations of relapse-related SNPs with pharmacokinetic and pharmacodynamics of antileukemic drugs offer plausible mechanism by which they are linked to treatment outcome. Finally, we aim to identify SNPs that are related to both genetic ancestry and relapse which are likely to contribute to racial disparities in ALL survival.

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• ASsessing and Predicting Infant RSV Effects and Severity (AsPIRES) Study

  A prospective multi-year clinical translational study including three cohorts of term infants experiencing their first Respiratory Syncytial Virus (RSV) season. All infants are less than or equal to nine months of age at study entry. The three subject cohorts represent the full spectrum of RSV disease severity and include a birth cohort, a cohort of infants hospitalized for RSV disease and infants evaluated at ambulatory settings for RSV infection. All infants are followed longitudinally and evaluated at recognition of acute RSV infection and twice during convalescence. Innate and adaptive immune status are comprehensively measured in association with clinical, environmental, viral, and bacteriologic factors. Genome-wide expression is assessed in the nasal airways, and in sorted peripheral blood lymphocytes. The study goal is to Identify host responses to RSV infection and factors associated with severe disease.

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• Admixture Mapping of Staphylococcus aureus Bacteremia

  In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia (SAB) in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.

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• A Multimodal Atlas of Human Brain Cell Types

  "A multimodal atlas of human brain cell types" includes sample data targeting two cell types that show species differences between mouse and human. First, it includes a detailed transcriptomic, morphological, and electrophysiological characterization of cell types in layer 1 of human middle temporal gyrus, focusing primarily on different inhibitory cell types. This project also includes gene expression data collected from nuclei in layer 5 of human fronto-insula, with a goal of identifying transcriptomic signatures of Von Economo neurons. Control samples collected as part of the same experiment are also included in the data set. This study was conducted as part of a collaboration between the Allen Institute for Brain Science, the University of Szeged, and the J. Craig Venter Institute. Collaborators request that publications resulting from these data cite their original publication: Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type (PMID: 30150662).

  Study phs001791

• The Ultrasound Study of Tamoxifen

  The Ultrasound Study of Tamoxifen is a 12-month longitudinal study to describe volumetric breast density change over time among women with and without tamoxifen exposure. Women were enrolled at the Karmanos Cancer Institute and Henry Ford Health Systems in Detroit, Michigan between 2011-2014. Enrollment included women prescribed tamoxifen for clinical indication (n=82) and a comparison group of women frequency matched on age, race, and menopausal status (n=165). Whole breast ultrasound tomography (UST) scans were used to measure volume averaged sound speed (m/s) as a surrogate of volumetric breast density. Ultrasound tomography (UST) scans were completed at baseline prior to tamoxifen initiation and were repeated at 1-3 months, 4-6 months, and 12 months after tamoxifen initiation. For the comparison group, UST scans were completed at baseline and 12 months. Questionnaires were completed at each scan.

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• CRISPR-Mediated ASD Gene Knockout Reduces Neuronal Activity

  Autism Spectrum Disorder is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of 10 ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNAseq revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory post-synaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.

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• Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma (DIPG)

  Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.

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• NHLBI TOPMed: Boston Early-Onset COPD Study

  Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This project collected a set of extended pedigrees ascertained through subjects with severe, early-onset COPD. This study has enrolled subjects with severe COPD (forced expiratory volume in one second (FEV1) < 40% predicted) at an early age (< 53 years) without alpha-1 antitrypsin deficiency (a known Mendelian risk factor for COPD). Extended pedigrees are enrolled, primarily in New England, although some more geographically distant subjects have been included. This study has been used for epidemiological studies, familial aggregation analysis, linkage analysis, and candidate gene association analysis. Approximately 80 of the severe, early-onset COPD probands will undergo whole genome sequencing in this project with sequencing data available through dbGaP.

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• Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA)

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. Advances in genetic and genomic technologies have revolutionized gene discovery for several complex diseases, but going to the next step in gene discovery for asthma among populations of African descent requires considering unique characteristics of this ethnic group, including adequate sample sizes and population stratification due to (European and African) admixture. Thus far, coverage of common genetic markers both in public databases and commercially available SNP chips has been inadequate to detect and measure genetic associations among African admixed populations. The aim of this study was therefore to catalog genetic diversity in populations of African descent, especially those whose ancestry reflects the African Diaspora in the Americas.

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• eMERGE III: Columbia GENIE (Genomic Integration with EHR)

  The Columbia GENIE study contributes and shares phenotype and genotype data for individuals who were treated with our healthcare facilities and consented to share their data with dbGaP for scientific discovery. Some of these individuals have kidney or neurological problems and some are healthy volunteers from the Washington Height patient community. The purpose of this NOMAS study is to obtain information about physical features of the brain, carotid arteries, and heart. Some of our patients are pediatric patients with cardiac conditions. The study sample consists of four patient cohorts: Northern Manhattan Study (NOMAS), N=1072 Pediatric Cardiac Genomic Consortium (PCGC), n=374 Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease (Caribbean Hispanics/AD), n=330 Alzheimer's Disease Sequencing Project (ADSP, n=44) Genetics of Chronic Kidney Disease Study, n=1256

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• Childhood Cancer Data Initiative (CCDI): Identification and Targeting of Treatment Resistant Progenitor Populations in T-cell Acute Lymphoblastic Leukemia

  Our goal with this study was to identify the mechanisms of treatment resistance in T-cell acute lymphoblastic leukemia (ALL) using single-cell genomics. We profiled 40 T-ALL cases from the Children's Oncology Group AALL0434 clinical trial using CITE-seq/snATAC-seq, capturing a breadth of immunophenotypes, including early T-cell precursor (ETP) and near-ETP/non-ETP subtypes. By integrating analyses of T-ALL cells with the normal T-cell developmental trajectory, the study identified a specific subgroup of leukemia cells resembling bone marrow progenitors (BMP-like cells). These BMP-like cells were associated with treatment failure and poor overall survival in T-ALL patients. Overall, this study reveals comprehensive multiomic signatures for rapidly assessing risk and tailoring targeted treatment for high-risk T-ALL patients.

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• Gene Variants in Pheochromocytoma and Paraganglioma

  Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla and in extra-adrenal locations, respectively. PPGL has the strongest hereditary risk of all endocrine neoplasms with about 40% of cases harboring germline mutations and another 25-30% of cases arising from somatic mutations. To date, over 20 susceptibility genes have been suggested to play a role in PPGL pathogenesis, with more genes still being researched. This project will seek to identify new candidate genes in apparently sporadic PPGLs to reveal a possible genetic background in cases without variants in known susceptibility genes. Knowledge of the genetic background and the genes involved in the pathogenesis of PPGL allows for clustering and/or development of targeted therapies for the tumors that cannot be surgically resected or tumors that have metastasized.

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• The Contribution of De Novo Coding Mutations to Meningomyelocele

  Meningomyelocele (MM) is considered a genetically complex disease resulting from the failure of the neural tube to close; a neural tube defect (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but most risk remains unexplained. 851 MM trios were recruited and we found 187 likely gene disrupting or damaging missense de novo mutations (DNMs) that are estimated to contribute to disease risk. These DNMs collectively define networks including actin cytoskeleton and microtubule-based processes, axon guidance, and histone modification. Gene validation demonstrates partial or complete loss of function, impaired signaling and defective neural tube closure in Xenopus embryos. Our results suggest DNMs make key contributions to MM risk, and highlight critical pathways required for neural tube closure in human embryogenesis. Data for 245 WES trios and 1 quad are available through dbGaP.

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• Transgenerational Transmission of Post-Zygotic Mutations Suggests Symmetric Contribution of First Two Blastomeres to Human Germline

  Skin and blood samples were collected from four phenotypically normal individuals (mother, father, and children) from a randomly selected family. Whole genomes of the samples from these individuals were sequenced to a depth of 30X-200X. Sequencing data for the mother was previously analyzed and is available at NDA collection #2961. Sequenced reads from the children and father were aligned to the human reference genome (hg19) generating BAM files for each individual. We used post-zygotic mutations in the mother to trace cell lineages across human generations. Analysis of this family demonstrated that different cell lineages were transmitted to offspring. Coupled with analysis of publicly available data, this result revealed a fundamental difference between soma and germline in lineage allocation and suggested a 50:50 contribution of the first two blastomeres to the germline.

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• Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

  In this study, the genomic landscape of extracutaneous juvenile xanthogranuloma (JXG) was analyzed. By leveraging the Dutch Nationwide Pathology Databank (Palga), tumor samples were obtained from different academic medical centers in the Netherlands. The study was approved by the Palga Scientific Council and Privacy Committee (LZV-2016-183) and the Institutional Review Board of Leiden University Medical Center (B19.074). In addition, the study was approved by the Biobank and Data Access Committee of the Princess Máxima Center for Pediatric Oncology (PMCLAB2024.0512). Provided are whole transcriptome sequencing (WTS) data of 3 histiocytic tumors with CLTC::SYK fusions. WTS was performed in the routine workflow of the Princess Máxima Center for Pediatric Oncology (as described in Hehir-Kwa, et al. JCO Precis Oncol 2022). RNA was derived from formalin-fixed paraffin-embedded tumor tissue (n=1) or from frozen tumor tissue (n=2).

  Study EGAS50000000584

• Whole-genome sequencing of BRCA-mutant breast cancer patient samples from tumour, germline tissue and plasma

  The use of circulating tumor DNA (ctDNA) to profile mutational signatures presents a non-invasive opportunity for understanding cancer mutational processes. In this study we developed MisMatchFinder, a liquid biopsy approach for mutational signature detection using low- coverage whole-genome sequencing of ctDNA. Through analysis of plasma samples across multiple different cancers, we demonstrated that MisMatchFinder accurately infers single-base and doublet-base substitutions as well as indels to enhance detection of ctDNA and clinically relevant mutational signatures. This study contains fastq files from whole-genome sequencing of temporally matched tumour (fresh frozen biopsies), blood germline and plasma samples collected from a BRCA1-mutant breast cancer patient to directly compare mutation signature analysis using gold-standard tumour-germline paired variant calling with our novel ctDNA-based method (MisMatchFinder).

  Study EGAS50000000569

• Transcriptomic profiles of tumor samples from patients with stage I-III TNBC treated with anthracycline-taxane chemotherapy plus fasting-mimicking diet plus/minus metformin in the context of the BREAKFAST trial (NCT04248998)

  BREAKFAST is a randomized, non-comparative, phase II trial enrolling stage I-III (cT>1cm) TNBC pts treated with neoadjuvant doxorubicin-cyclophosphamide q3w for 4 cycles, followed by weekly paclitaxel for 12 cycles. Pts were randomized 1:1 to receive: CT + triweekly 5-day FMD cycles (arm A), or CT + FMD + daily metformin (1700 mg) (arm B). The primary study objective was to investigate if one or both experimental treatments were able to increase pCR rates when compared to anthracycline-taxane CT alone according to historical data. Secondary/exploratory endpoints included biomarker analyses based on tumor transcriptomics analyses. Specifically, we collected fresh-frozen tumor samples at baseline and 14-21 days after the first treament cycle and we analyzed the RNA-seq profiles to identify early predictors of treatment activity.

  Study EGAS50000000690

• Methylation-Based Immune Deconvolution in Prostate Cancer Patients Before and After Radical Prostatectomy

  To explore whether surgical treatment for prostate cancer leads to long-term immune changes, we conducted a pilot study of n=11 prostate cancer patients treated with radical prostatectomy. We also included n=8 patients managed with active surveillance as a comparison group. We examined intra-individual changes in circulating immune cell subsets using serial blood samples collected pre- and approximately 6-months post-prostatectomy, and from matched time points for the patients managed on active surveillance. Immune cell subsets were deconvoluted using genome-wide methylation data. We observed no meaningful changes in circulating immune cell subsets in either patient group, suggesting that any surgery-induced immune changes to the circulating immune profile may not be long-lasting. The genome-wide methylation data from the two time points will be made available through dbGaP.

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