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• Whole exome sequencing data for patients with Bosma arhinia microphthalmia syndrome (BAMS).

  The datasets includes 21 samples from 7 families with Bosma arhinia microphthalmia (BAMS). For details of the study please refer to the manuscript "De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development", Nature Genetics 2017. Each sample was exome sequenced and the family ID in sample description refers to the Individual ID in Supplementary figure 2 of the manuscript.

  Study EGAS00001002193

• We evaluate the PGD/PGS including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities.

  A total of 395 couples were subjected to IVF-PGD treatment, including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities. The NGS test was performed using low coverage whole genome sequencing with HiSeq 2000 platform. And the SNP array test was using Affymetrix Gene Chip Mapping Nsp I 262K.

  Study EGAS00001000981

• DNA sequencing for human normal endometrial glands

  To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we conducted whole-exome and whole-genome sequencing for 56 endometrial glands and matched blood samples from 4 women. By collecting endometrial glands from different parts of the endometrium, we showed that multiple glands with the same somatic mutations occupied substantial areas of the endometrium.

  Study EGAS00001005822

• PCA Atlas Chromium scRNA-seq and demultiplexing support (FASTQs, BAMs, capture-level VCFs and mapping tables)

  This dataset contains Chromium single-cell RNA-seq data and demultiplexing support for the PCA Atlas study EGAS00001008332. Included data objects: - 16 Chromium scRNA-seq FASTQ runs (EGAR accessions) for captures PCa1–PCa16. - 16 aligned BAM analyses (one Cell Ranger possorted_genome_bam.bam per capture). - 16 capture-level genotype VCF analyses derived from the Axiom UK Biobank array, used as demultiplexing panels. - demux_map.csv (EGAZ00001945520): donor–capture–sample mapping for genotype-based demultiplexing. - chromium.csv (EGAZ00001945537): run-level mapping linking captures, EGA samples, runs (EGAR), experiments (EGAX) and BAM analyses. Together these objects provide a complete view of the Chromium scRNA-seq data and the genotype-based demultiplexing support needed to reproduce donor assignment and downstream analyses.See also https://zenodo.org/records/17372603

  Dataset EGAD00001015795

• PPGL WES dataset

  Dataset includes fastq files for WES experiments for tumor samples of PPGL patients. Paired end reads fastq files are available for 87 different samples

  Dataset EGAD00001008579

• Berlin Neuroblastoma Patient Genomic Data from Targeted Sequencing for Detection of TERT rearrangement breakpoints to monitor neuroblastoma

  Our objective was to establish a liquid biopsy-based monitoring strategy for pediatric high-risk neuroblastomas that are harboring genomic TERT rearrangements at diagnosis. TERT rearrangement breakpoints are detected by a hybrid capture-based neuroblastoma DNA panel sequencing (published in PMID: 34442335) in tumor material and are reflected in cell-free tumor DNA and can serve as robust biomarkers for disease activity. Within the dataset, 5 tumors of 4 pediatric patients with a neuroblastoma were DNA sequenced. Provided are FASTQ data files, bam and bambai files, as well as breakpoint spanning and encompassing read (enspan) bam and bambai files. Sequencing bam data files are aligned to GRCh37.p13 reference genome (processed).

  Dataset EGAD00001011088

• Paired RNA-Seq of fCAB treated and bisulfite treated VDH01, partly depleted for NSUN3

  Paired RNA-seq of bisulfite treated VDH01 samples control or depleted for NSUN3 (4 replicates each). The samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated vdh01 samples control or depleted for NSUN3(4 replicates each). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of bisulfite treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq.

  Dataset EGAD00001008742

• Targeted Validation Samples

  The dataset consists of targeted sequencing data obtained from an independent cohort of 11 patients to validate discriminative DMRs (differentially methylated regions) for Acute coronary syndrome (ACS) subtypes. The cohort includes 2 healthy subjects, 4 STEMI (ST-segment elevation myocardial infarction), 3 NSTEMI (non-ST-segment elevation myocardial infarction), and 2 UA (unstable angina) patients. The sequencing panel targeted 18,831 CpGs for analysis, reaching at least 5 reads coverage for 75% of the targeted CpGs in each sample. The sequencing was performed using the NEBNext Enzymatic Methyl-seq Module and the Nonacus Cell3TMTarget: Library Preparation kit, followed by probe hybridization, capture enrichment, and sequencing on the Novaseq 6000 platform, generating 400 million reads. The dataset is in raw fastq format.

  Dataset EGAD00001010934

• Machine Learning Guided Signal Enrichment for Plasma Tumor-burden Monitoring Dataset

  Includes 4 Datasets: 1. 35 Control Plasma WGS samples sequenced on NovaSeq V1.0 Chemistry at the New York Genome Center. Denoted by CTRL-2XX naming scheme. 2. Plasma WGS from 17 patients with Small Cell Lung Cancer. Samples extracted at either Pretreatment or Postoperative at weeks 2 or 3. Denoted by SCLC-XX naming scheme. 3. Plasma WGS from a synthetic mixing study of a high-burden melanoma plasma sample with plasma bag, at estimated tumor concentrations of 10e-3, 10e-4, 10e-5, and 10e-6 for 2 replicates. Denoted by SM-repX naming scheme. 4. Assorted Plasma, Tumor, and Normal WGS from patients with NSCLC expressing high-burden for use in model training. Denoted by NSCLC-2XX naming scheme.

  Dataset EGAD00001011352

• Computational approach to discriminate human and mouse sequences in patient-derived tumour xenografts

  Whole Exome Sequencing was performed in a dilution series containing known amounts of human and mouse DNA, 3x 100% human 0% mouse, 2x 90/10, 3x 50/50, 2x 25/75 and 3x 0/100. A set of breast cancer clinical samples, matched normal tissue and matched PDTXs (total number = 14) were also analysed. Paired-end 75bp sequences for the dilution series and paired-end 125bp for the clinical samples were obtained on Illumina HiSeq2500; fastq files are provided. A triplicate analysis of the transcriptome using RNA-seq was also performed for the Universal Human RNA Reference and the Universal Mouse RNA Reference samples. Paired-end 150bp fastq files obtained on Illumina HiSeq4000 are provided.

  Dataset EGAD00001003800

• CTN - 0051: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT)

  The overarching goal of CTN-0051 is to foster adoption of new relapse-prevention pharmacotherapies in community-based treatment programs (CTPs) where these could have a substantial public health impact. To this end CTN-0051 will assess the comparative effectiveness of extended-release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery. The study is conducted in 8 CTN-affiliated CTPs that provide or partner with detoxification services (inpatient/residential) which have the capacity to maintain participants opioid-free for approximately 3-7 days, have the capacity to provide medication-assisted therapy, and can provide a minimum of one group or individual counseling session per week during the 24-week treatment period. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). To maximize generalizability, the point of randomization is flexible, from shortly after program admission until just prior to program discharge. The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e., loss of persistent abstinence) during the 6-month trial. The primary outcome measure is the time to the event, with the event called relapse. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, (2) explore demographic, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

  Study phs002876

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization across Pediatric Brain Tumors and Other Solid and Hematologic Malignancies for Research, Diagnostic, and Precision Medicine

  This study contains tumor and germline WGS, RNA-Seq, Clinical Panel Sequencing, and other omics and molecular data for patients with pediatric brain tumors and other solid and hematologic malignancies. This data has been collected from multiple organizations including the multi-institute Children's Brain Tumor Network (CBTN), the Pacific Pediatric Neuro-Oncology Consortium (PNOC), and the Children's Hospital of Philadelphia Division for Genomic Diagnostics (CHOP DGD). In addition to being available pre-publication and without embargo via dbGaP and the NCI Cancer Research Data Commons, this data is made available via Cavatica, PedcBioPortal and the Kids First Data Resource Portal. Collectively, this availability strives to accelerate the research process and enable members of the scientific and patient communities to partner and make discoveries faster than ever before.In 2019, the CBTN launched the Pediatric Brain Tumor Atlas, which now comprises the largest collection of childhood brain tumor data in the world. This resource is helping accelerate not only brain tumor research, but is also empowering discovery for other rare childhood conditions. Brain tumors are the most common form of cancer in children aged 0-19 in the United States, and are the largest cause of cancer-related deaths. The estimated number of new cases in 2019 is nearly 3,800, and thus brain tumors are a rare disease. Despite their relative rarity, the years of potential life lost due to brain tumors in 2009 was estimated at 47,631 years for children and adolescents aged 0-19 in the United States; this is a disproportionate amount of life lost compared to adult cancers and represents an unrecognized societal threat. There is an urgent need to improve therapies for these children. This sequencing cohort defines the largest, clinically annotated pediatric brain tumor cohort study to date and seeks to define the intersection of germline and somatic underpinnings of pediatric brain tumors across a shared developmental context of cancer and structural birth defects.

  Study phs002517

• Genome-Wide Association Study of Genetic Susceptibility for Graft-vs-Host Disease Cohort 1

  Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, gastrointestinal (GI) tract, and liver in recipient. More than half of all Allo-HSCT recipients develop different degrees of GVHD (grades I-IV). About 20% of recipients develop severe GVHD (grades III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in human leukocyte antigen (HLA) haplotypes that are routinely checked for donor selection. Even when donors and recipients are HLA-identical, many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent Allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP and Medical College of Wisconsin. In the second aim, we will validate the association between high risk genotypes detected in the first aim and severe GVHD in 1,750 donors and 1,750 recipients of Allo-HSCT, and perform the joint analysis with the discovery samples. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an ex vivo surrogate for an alloimmune response.

  Study phs002185

• Personalized Medicine Strategy for MPNSTs: Using Precision Oncology on PDOX Models to Inform Tumor Boards

  Background: Malignant peripheral nerve sheath tumors (MPNSTs) are a heterogeneous group of aggressive soft tissue sarcomas with poor prognosis. Currently there is a lack of effective treatments for MPNSTs. Here, we propose a personalized medicine approach that integrates a precision oncology strategy guided by MPNST genomic analysis, with a functional validation of treatment response in an orthotopic xenograft model (PDOX) derived from the same MPNST. Methods: Comprehensive whole genome sequencing analysis was performed in primary MPNSTs, relapses and (in one case) metastases, following disease progression in two independent individuals. Matched MPNST PDOX models were generated by orthotopically implanting tumor fragments near the sciatic nerve of immunodeficient mice. Candidate targeted combination therapies were prioritized based on genomic alterations and tested in vivo in the PDOX models. Results: The feasibility of the developed strategy is illustrated for two MPNST patients, one Neurofibromatosis type 1 (NF1) individual that developed two independent MPNSTs and another sporadic MPNST case with multiple metastatic relapses. Genomic analysis revealed a remarkable degree of genomic stability across primary MPNSTs and their successive relapses in each patient, and even metastases in one individual. While based on a small number of cases requiringing additional analyses, this finding aligns with previous evidence suggesting a fair genomic conservation throughout tumor evolution. This stability supports the identification of consistent therapeutic vulnerabilities throughout disease progression. Among the therapies tested, co-treatment of MEK inhibitor (MEKi) plus bromodomain inhibitor (BETi) elicited the highest antitumor activity, resulting in approximately 60% tumor volume reduction in the sporadic MPNST PDOX model, whose patient has been receiving this therapy for eight months with sustained remission. Conclusions: This study demonstrates the feasibility and clinical utility of integrating genomic-driven precision oncology with PDOX-based functional testing for MPNSTs. This strategy may support molecular tumor boards (MTBs) in their treatment decisions. The observed genomic stability supports the use of longitudinal tumor profiling to guide treatment, and the success of MEKi+BETi highlights its potential as a combination therapy for MPNSTs.

  Study EGAS50000001502

• Identification of intronic sequences promoting natural skipping of ABCA4 exon 15 using long-read transcriptomics and midigene assays

  Stargardt disease is an inherited retinal disease that leads to progressive loss of vision, and is caused by biallelic variants in the ABCA4 gene. A significant proportion of ABCA4 variants of variable penetrance affect pre-mRNA splicing. Previously, we observed the exclusion of certain ABCA4 exons into the final transcript in the absence of any disease-causing variants. In this study, we explored this phenomenon that we coined natural exon skipping (NES) for the entire ABCA4 transcript, using targeted RT-PCR analysis as well as long-read transcriptome sequencing of control retina samples. For the most abundant NES event, which is skipping of ABCA4 exon 15, overlapping ABCA4 deletion constructs were employed to identify responsible cis-regulatory sequence motifs. Subsequently, antisense oligonucleotides (AONs) were designed and tested to reverse NES and restore fully-spliced ABCA4 mRNA. We identified intronic regions on each side of exon 15 that, when deleted, increased the inclusion of exon 15 in the final transcripts. Interestingly, these motifs appear to work in a synergistic manner. Further fine-mapping of these regions revealed several cis-regulatory motifs that may be responsible for inducing NES, on each side of the exon. AONs targeting these motifs unfortunately did not decrease the skipping of exon 15. In conclusion, we discovered an intriguing phenomenon that, in the absence of disease-causing variants, results in the skipping of one or more exons in the ABCA4 transcript. These NES events appear to be regulated by cis-regulatory motifs within the flanking introns. This work captured the extend of NES throughout ABCA4 transcript and the role of cis-regulatory motifs in pre-mRNA splicing.. The use of AONs targeting cis-regulatory motifs is an innovative strategy for splicing modulation, suitable for complementing future variant-specific splicing modulation therapies in ABCA4 retinopathies.

  Study EGAS50000000071

• Genetic Studies of Chronic Kidney Disease (CKD)

  The Genetic Studies of Chronic Kidney Disease (CKD) is an ongoing genetic research and biobanking protocol which aims to elucidate the genetic basis CKD. The study recruits patients seen at the Columbia University Medical Center (CUMC) Nephrology Division for the evaluation and care of CKD. All patients clinically diagnosed with CKD are eligible to participate; there are no inclusion or exclusion criteria related to age, sex/gender, and/or race/ethnicity. In addition to office visits, patients are recruited in contexts including perinatal care and nonprofit events for patients with various forms of CKD; recruitment tools include bilingual informational brochures, flyers, and consent forms. All individuals provide informed consent; for minors, signature of the parent/guardian is required. Consent includes: use of biosamples given for genetic studies, and the request to be re-contacted if medically actionable genetic findings are identified. In the case of the latter, such research-level findings are first validated in a clinically certified (CLIA) laboratory environment, using a second sample given by the individual at the time of re-contact; following CLIA validation, the individual is once again re-contacted, and, assuming he or she still desires return of these results, they can then be returned. Following the above consent process to participate in the study, individuals provide a single biosample (generally, a venous blood sample), from which DNA is extracted using standard protocols and used for genetic studies, such as exome sequencing. Basic clinical and demographic data, including sex/gender, age, and race/ethnicity are also collected. All data collected is stored in a secure computerized database, with patient samples anonymized using numerical identifiers; the relation of this identifier to patients' names is kept in a locked computer file in a centralized database. Electronic data complies with all HIPAA and other privacy and security regulations, and resides on a firewall server maintained by the CUMC IT department.

  Study phs001828

• Women's Health Study Accelerometry Dataset

  Background The Women's Health Study (WHS) was a randomized trial testing low-dose aspirin and vitamin E for preventing cancer and CVD among 39,876 women aged ≥45 years throughout the US from 1992-2004. When the trial ended as planned, women who were willing to participate continued in an observational follow-up study. Participants in Accelerometer Study From 2011-2015, an ancillary study collected data on physical activity and sedentary behavior using accelerometers. Women were mailed a triaxial accelerometer (ActiGraph GT3X+, ActiGraph Corp) with a wear log, and asked to wear this on their hip for seven consecutive days, removing it only during sleep and water-based activities. Further details have previously been published (PMID: 30666321). A total of 17,708 women wore and returned their devices, and data were downloaded from the devices of 17,466 women; no data were available from the other 242 (device failure). By convention, a "valid day" of wear has data on at least 10 hours (PMID: 22698174). Among these 17,466 women, 17,062 had at least one valid day of wear. The data are provided for all 17,062 women. Additionally, "compliant wear" is conventionally defined for participants wearing the device for at least 10 hours, on at least 4 days (PMID: 22698174). Of the 17,062 women, 16,741 had compliant wear (PMID: 29109088). Self-reported Physical Activity and Sedentary Behavior After we received the accelerometer from a WHS participant, she was sent a questionnaire asking her to report the time she spent in different physical activities during the week that the accelerometer was worn (see questionnaire below). A total of 15,514 women (91% of participants in the Accelerometer Study) returned their physical activity questionnaires. In addition, beginning in October 2012, we included questions on sedentary behavior; a total of 9,430 women returned questionnaires that included questions on both physical activity and sedentary behavior.

  Study phs001964

• Wistar PDX Development and Trial Center

  Overall the outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas. These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof-of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies, over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical, histological, and genetic heterogeneity of this disease. Our collection of PDX models represents one of the largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately recapitulates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued expansion of our robust melanoma PDX collection to identify new therapeutic approaches that fill important clinical gaps in this disease.

  Study phs002432

• Polycystic Ovary Syndrome (PCOS) Genetics

  PCOS is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below. NUgene project: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.

  Study phs000368

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• Foundation Medicine Adult Cancer Clinical Dataset (FM-AD)

  The Foundation Medicine adult cancer clinical dataset consists of 18,004 unique solid tumor samples that underwent genomic profiling on a single uniform platform as part of standard clinical care. The dataset is derived from the FoundationOne® genomic profiling assay version 2 that interrogates exonic regions of 287 cancer-related genes and selected introns from 19 genes known to undergo rearrangements in human cancer. Genomic DNA samples were sequenced to over 500x median coverage, and custom computational analyses identified all classes of genomic alterations (base substitutions, insertions and deletions, copy number alterations, and rearrangements). Since matched normal tissue was unavailable for analysis, these data underwent additional filtering to enrich for cancer-related events. The reported data includes genomic alterations that are known and suspected tumor drivers, as well as variants of unknown significance. To preserve patient anonymity, all known or suspected germline variants were removed from the data unless known to be associated with cancer development. The dataset contains genomic alteration profiles generated by FoundationOne version 2 testing for adult cancer patients (over 18 y.o.), and represents a vast diversity of tumor subtypes, including many rare diseases not profiled as part of large-scale profiling efforts. Cases are grouped into 16 broad disease categories containing tumors from 162 unique disease subtypes. Since specimens were profiled as part of clinical care, limited clinical parameters were available, including age, gender, tissue of origin, % of tumor nuclei, and diagnosis. Publication of this dataset is intended to allow the broad scientific community access to this unique cohort for use in scientific research projects of common and rare types of cancer, both for generating leads regarding causal mechanisms as well as cross-testing and confirming existing hypotheses. A pediatric cancer clinical dataset consisting of data from 1,215 patients under 18 y.o. is available separately at: FOUNDATION MEDICINE

  Study phs001179

• Small RNA Contents of Extracellular Vesicles from Patients with Cognitive Decline

  In this proposal, we examined samples from living neurologically normal individuals (n=72), cognitively normal Parkinson's disease (PD; n=21), PD with mild cognitive impairment (PD-MCI; n=18), PD with dementia (PDD; n=23), and dementia with Lewy-bodies (DLB; n=18), Alzheimer’s disease (AD; n=33) and mild cognitive impairment (MCI, n=38). The main goal for this study was to assess the diagnostic utility of small RNA contents from extracellular vesicles (EVs) for the prediction of cognitive decline. Plasma samples were collected and the RNA from extracellular vesicles (EVs) was isolated using the Qiagen exoRNeasy kit, and the small RNA contents were sequenced using the PerkinElmer NextFlex kit (v2). While PD is typically thought of as a motor disorder, there are significant non-motor symptoms that can be devastating. One of the most common non-motor symptoms of PD is dementia (PDD). While PD subjects that develop dementia all have Lewy bodies, there is often co-pathology with tau and β-amyloid found at autopsy or by PET amyloid imaging; thus, subjects diagnosed with AD were also included in the study. The development of the category, mild cognitive impairment (MCI) in AD, and in PD, provides an opportunity to identify and examine a transitional state between normal aging and dementia; this is a patient population ideally suited for therapeutic intervention. Progress in the detection, validation, and standardization of molecular biomarkers from biofluids, such as extracellular RNAs (exRNAs), would be efficient and cost-effective aids in the assessment of disease progression, cognitive decline, and response to therapeutics. We have provided the raw fastq files for the sequencing data from each sample. We are also providing demographic information, as complete as we have for each person; including age, diagnosis, sex, and cognitive assessments.

  Study phs003300

• Childhood Cancer Data Initiative (CCDI): Genomic Analysis in Pediatric Malignancies

  Pediatric solid tumors are highly heterogeneous, encompassing a large number of histotypes. The genomic landscape of these diseases is characterized by few single-nucleotide variants (SNVs) compared to adult cancers. In contrast, many exhibit a high prevalence of structural or epigenetic changes that alter gene expression, underlining the need for comprehensive genomic approaches such as whole-genome sequencing (WGS). Several studies have specifically addressed the clinical utility of genomic analysis in the pediatric and AYA cancer setting. Review of these studies point to key challenges that must be addressed in order to advance the routine use of genomics in this population. We have established a large collection of solid tumor tissue samples through our biobanking efforts. Where possible, we obtain longitudinal samples from the same patient. These primary patient samples and their corresponding germline have been analyzed using whole genome and whole transcriptome sequencing methods and have been linked to clinical metadata using both manual curation and robust methods for automatic extraction from the electronic health record (EHR). Importantly, research-grade genomic analysis is performed in parallel to our CLIA-grade sequencing (“UCSF500”) efforts for some of the patients in this study cohort and have been submitted as part of the American Association for Cancer Research's project GENIE and/or the National Childhood Cancer Registry. For our sequenced tumor samples, we have retrospective clinical data and ongoing efforts to prospectively record key events throughout the patient's cancer journey. In our solid tumor program, we have developed many patient-derived xenograft models and a number of PDX-derived cell lines. These unique models have been evaluated using genomic and functional approaches including (in some cases) treatment with conventional chemotherapy or investigational agents. Lastly, these samples were collected from a population that is among the most diverse in the nation and includes significant numbers of Asian, Latino, Indigenous and African-American patients, groups that are traditionally underrepresented in many banking efforts.

  Study phs002430

• Genomic Profiling of Pediatric Tumors by Cell Free DNA Sequencing

  BACKGROUND Analysis of cell-free DNA (cfDNA) from peripheral blood has been studied extensively for detection and monitoring therapy response in adult cancers, but utility in pediatric tumors is unclear. METHODS We studied 233 children with hematologic, solid and brain tumors. cfDNA was extracted from 1 mL of plasma collected at diagnosis. Circulating tumor DNA (ctDNA) in cfDNA was quantified and diverse classes of somatic genomic variants were detected using PeCan-Seq. PeCan-Seq findings were compared with matched tumor whole-genome and whole-exome sequencing data. Minimal residual disease (MRD) status was evaluated by cfDNA PeCan-Seq in 14 patients with B-cell acute lymphoblastic leukemia. RESULTS Plasma cfDNA yields at diagnosis were higher for hematologic malignancies than for solid and brain tumors. Patients with hematologic malignancy were 100% ctDNA-positive, the median ctDNA fraction in cfDNA was 0.77. We detected 97% variants that were present in tumors and covered by the capture panel, and 50 subclonal variants that were present in cfDNA only. Our approach enabled detection of sequence and structural variants in B-ALL ctDNA at varying levels of MRD. Nineteen of 38 patients with solid tumors were ctDNA-positive, with high prevalence in Ewing Sarcoma, liver tumors and osteosarcoma. One of 19 brain tumor patients was ct-DNA positive, indicating lack of utility for plasma-derived cfDNA in this disease. Notably, cfDNA analysis of a single plasma sample identified genomic features in ctDNA derived from B-ALL, concurrent primary neuroblastoma, and a later neuroblastoma relapse, indicating that genomic variations from multiple tumors could be detected simultaneously. CONCLUSIONS Pediatric patients with hematologic malignancy had an abundance of plasma ctDNA at diagnosis. Plasma ctDNA levels varied between different solid tumor types, more studies are needed to determine utility. Panel-based cfDNA sequencing could serve as a non-invasive approach for pediatric cancer diagnosis and disease monitoring.

  Study EGAS50000000072

• Single-Gene vs. Panel Sequencing in Advanced HR+/HER2− Breast Cancer

  Background: Hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer is the most common subtype of breast cancer, with biomarker-driven therapies improving outcomes. Liquid biopsies, which analyze circulating tumor DNA (ctDNA), are increasingly essential in clinical management, offering a minimally invasive approach to assess somatic alterations and guide therapy decisions. However, the choice of assay directly affects clinical utility and global access to validated testing platforms remains inconsistent. To address these challenges, this study aimed to compare the performance of single-gene and panel-based sequencing for detecting PIK3CA mutations in HR+/HER2− breast cancer and evaluate the added value of broader genomic profiling in guiding treatment decisions. Patients and methods: We conducted a prospective, multicenter study comparing our previously established SiMSen-Seq (SSS) assay, a single-gene method targeting PIK3CA hotspot mutations, with the AVENIO ctDNA Expanded assay, enriching for 77 clinically relevant cancer genes. Additionally, tumor fractions were estimated with mFAST-SeqS by assessing chromosomal aneuploidy. We analyzed 161 plasma samples collected from 146 patients with HR+/HER2− advanced breast cancer before starting a new line of palliative therapy. Results: High concordance (92.6%) was observed between SSS and AVENIO for PIK3CA mutation detection, with accurate variant allele frequency (VAF) quantification confirmed by Bland-Altman analysis and linear mixed-effects modeling. AVENIO identified additional PIK3CA mutations in 19% of samples as well as other actionable alterations, including ESR1 mutations (17.5%) and PI3K pathway alterations (40.6%). Panel sequencing improved the interpretation of negative liquid biopsy results by integrating tumor fraction and VAF metrics. Conclusions: Panel sequencing assays such as AVENIO provide broader genomic coverage, enhance the detection of actionable mutations and refine the interpretation of negative liquid biopsy findings. These findings support the integration of comprehensive ctDNA profiling into routine clinical practice for HR+/HER2− advanced breast cancer while highlighting the need for improved assay accessibility and expanded genomic targets.

  Study EGAS00001008200