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• Detroit Research on Cancer Survivors (ROCS) and Disparities and Cancer Epidemiology - Colorectal Cancer (DANCE)

  The goals for this study were as follows:1. Enroll a total of 5,060 African Americans newly diagnosed with cancer into the Detroit Research on Cancer Survivors (Detroit ROCS) Cohort. These population-based cases will be ascertained through the Detroit Metropolitan Detroit Cancer Surveillance System (MDCSS), a founding member of the NCI SEER Program. Participation at baseline will include a written, web-based, or telephone interview, saliva and/or blood collection, and tumor block retrieval, with detailed cancer-related information coming from the MDCSS registry and medical records.2. Enroll a subgroup of colorectal cancer patients identified through the Louisiana Tumor Registry (LTR). An additional 500 colorectal cancer patients, approximately half non-Hispanic white and half African American, will be identified through the LTR and enrolled into the ROCS protocol. The survey is the same survey administered to the ROCS cohort. The Louisiana (“DANCE-CRC”) cohort will not be followed beyond baseline, and blood will not be collected (tumor tissue, however, will be collected, deidentified, and sent for processing through Dr. Rozek's laboratory at Georgetown University).The proposed cohorts will provide for a broad research agenda evaluating cancer outcomes in African Americans across a variety of factors from individual, provider, health care system and community perspectives. These factors include tumor characteristics driving individualized treatment planning, quality of life after a diagnosis and recurrence. Utilizing the MDCSS registry, we will enroll a large population-based sample of African-American cases with lung, breast, colorectal, and prostate cancers and their caregivers resulting in a cohort that will provide substantial benefit to the cancer research community. KCI has a strong history of research in the African-American community and the faculty represents a breadth of experience that includes clinical oncology, genetic epidemiology, environmental exposures, quality of life, treatment decision making, racism/discrimination, and health behaviors. Drs. Schwartz and Beebe-Dimmer have been and will continue to be generous collaborators with other institutions to ensure that this resource will be extensively utilized. The proposed overall cohort will be the only one of its kind, to our knowledge, filling a substantial gap in our understanding of the determinants driving cancer outcomes in African Americans. In addition to registry data detailing cancer specifics, yearly surveys have collected information about individualized treatment experiences, heath histories, family histories, quality of life after a diagnosis, recurrence and caregiving. Population: Adult cancer survivors (see inclusion criteria in next section) Molecular Technologies: Genotyping: Infinium Expanded Multi-Ethnic Genotyping Array (MEGAEX) DNA Sequencing: Illumina NovaSeq X Plus using XLEAP-SBS (sequencing by synthesis) Whole genome sequencingPrincipal Findings: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Variants in DNA damage repair genes and HOXB13 may be important cancer risk factors for Black men diagnosed with prostate cancer, and are more frequently observed in men with a family history of cancer. ROCS participants reported high rates of a family history of cancer. The high rate of eligibility for Cancer genetic counseling among ROCS participants supports the need for interventions to increase referrals and uptake of genetic counseling among African Americans 60% of ROCS participants reported participating in regular physical activity (PA), with 24% reporting ≥150 min/wk. There were no differences by sex, but prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely. Survivors who reported participating in regular PA reported higher health-related quality of life and lower depression. More African American than White survivors reported financial hardship and limiting care. More White than African American survivors reported utilizing assets, while more African American survivors reported cancer-related debt. Data available in dbGaP: Individual phenotype data Individual genotype data Individual sequencing dataSample types: Germline DNA

  Study phs003116

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• Broccoli Sprouts Extracts Trial (BEST-COPD-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To establish a safe and tolerable dose of sulforaphane that effects in vivo antioxidants via Nrf2 for development as a potential novel treatment for participants with Chronic Obstructive Pulmonary Disease (COPD).Background: Chronic Obstructive Pulmonary Disease (COPD), caused primarily by smoking, is the third leading cause of death in the United States and world-wide. Surprisingly, there are few treatments available to address the pathobiology of COPD other than cessation of smoking. The development and progression of COPD are associated with increased inflammatory response(s) and increased oxidative stress in the lung. Thus, one approach to the development of novel therapies is the stimulation of endogenous antioxidant defense mechanisms.Nuclear factor erythroid-2-related factor 2 (NFE2L2/Nrf2) is a transcription factor activated by oxidative stress. Nrf2 activity promotes anti-oxidant enzymes, and anti-oxidant enzymes play key roles in cellular defenses. Sulforaphane, a derivative of broccoli and other cruciferous vegetables, has been shown to stimulate Nrf2 activity in both in vivo and in vitro experiments. For example, activation of Nrf2 protected mice from developing emphysema after chronic smoke exposure and decreased oxidative stress. Similarly, activation of Nrf2 in human COPD lung cells resulted in decreased oxidative stress. Therefore, this study was designed to assess whether daily ingestion of sulforaphane by COPD participants for four weeks increased Nrf2 activity in alveolar macrophages and bronchial epithelial cells. Participants: There were a total of 89 participants randomized to one of three treatment arms. Of these, 31 participants were randomized to the placebo arm, and 29 participants were randomized to the each of the sulforaphane arms. One participant withdrew from the placebo arm, therefore, a total of 88 participants completed the study.Design: Participants were assigned to receive sulforaphane at 25 micromoles (4.4mg), sulforaphane at 150 micromoles (26.6 mg), or placebo (microcellulose) once daily by mouth. Computer-generated treatment assignments were blinded to participants, clinical staff, and study staff. Doses were back-filled with methylcellulose and presented in similar capsules to compensate for appearance and weight differences in sulforaphane and placebo treatments arms.There were a total of five study visits over the six-week study period. Prior to randomization, participants were assessed for eligibility, which included baseline data collection. Participants provided medical histories, underwent a physical examination, pre-and-post bronchodilator spirometry, lung volume measurements, carbon monoxide diffusing capacity (DLCO), and pulse oximetry over the six-week study period. Follow up data and biospecimens were collected at the final visit, which was targeted for four weeks after randomization. Two fiberoptic bronchoscopies were performed under sedation to collect endobronchial brushings and bronchoalveolar lavage used to isolate alveolar macrophages and bronchial epithelial cells. The first bronchoscopy was performed on the day of randomization, and the second bronchoscopy was performed the day after the final visit. In addition, nasal brushings were obtained prior to bronchoscopy to isolate nasal epithelial cells. The primary outcomes were changes in Nrf2 target gene expression at four weeks in alveolar macrophages and bronchial epithelial cells. The target genes for the primary outcome were NQ01, H01, AKR1C1, and AKR1C3. Secondary outcomes included the evaluation of: expression of other genes in the Nrf2/Keap1 pathway (e.g. Nrf2/NFE2L2, KEAP1, and SLPI), markers of oxidative stress (e.g., isoprostane and thiobarbituric acid reactive substances) in plasma and expired breath condensate, and cytokine profiles in bronchoalveolar lavage fluid. Conclusions: Sulforaphane administered at four weeks doses of 25umoles and 150umoles to participants with COPD did not significantly increase Nrf2 target gene expression in alveolar macrophages or bronchial epithelial cells. In addition, changes in oxidative stress markers and the expression of other genes in the Nrf2/Keap1 pathway were not statistically significant between the treatment groups.Wise RA, Holbrook JT, Criner G, et al. Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. Vij N, ed. PLoS ONE. 2016; 11(11):e0163716. doi:10.1371/journal.pone.0163716 (PMID: 27832073; PMID: 28350841).

  Study phs004022

• Prader-Willi Syndrome and Early-onset Morbid Obesity Natural History Protocol

  This observational study will involve the comprehensive assessment of the medical, behavioral and nutritional history and the clinical features of individuals with Prader-Willi syndrome and individuals with features of PWS-like/EMO. A blood sample will be obtained from the participants in order to create a DNA and RNA repository. In those PWS participants with a known deletion a blood sample will be collected for DNA in order to perform array comparative genome hybridization (aCGH) microarray or Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) studies to characterize the extent of the deletion. DNA samples will be sent to the Consortium Center at Baylor College of Medicine for the performance of the aCGH studies and to either Dr. Driscoll or Dr. Butler lab for MS-MLPA analysis. No drugs or treatments will be administered through this protocol. Our goal is to enroll as many participants as possible over a 8 year period. Currently we have enrolled 297 total subjects of which 265 have PWS and 32 EMO. Our original goal was to have enrolled over the first 5 years a clinical database of 200 individuals with PWS and 100 with EMO. We have exceeded expectations in PWS enrollment, but have fallen short in the enrollment of individuals with EMO. Therefore, we would like to reset our goals. We now propose to have an enrollment goal of 400 total subjects of which 350 will have PWS and 50 will have EMO. Eligible participants will be initially enrolled in the natural history study from the 4 clinic sites currently involved with PWS (University of Florida, Kansas University Medical Center, Vanderbilt University and University of California at Irvine). Participants assessed will serve to provide a background of information and a willing cohort for future interventional studies. All participants will have had standard genetic testing at a commercial laboratory prior to entry into the study. The PWS participants will be classified into one of the 3 main molecular classes (deletion, UPD and ID). The EMO participants will have had laboratory testing ruling out PWS and chromosomal aneuploidy (e.g., trisomy 21, Klinefelter syndrome, etc.). Going forward we feel it is important that all newly recruited EMO subjects have an aCGH as part of their evaluation so we can identify those with discrete deletions, duplications or copy number variants (CNV) and compare them to those without aCGH abnormalities. The participants will be assessed annually (0-3 years of age) or biennially (> 3 years) in the Clinical Research Center (or equivalent facility) using standardized protocol including photographs for documentation purposes to compare the evolution of the clinical phenotype.

  Study phs000575

• Action to Control Cardiovascular Risk in Diabetes (ACCORD) Clinical Trial

  The Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial was a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type-2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. The purpose of ACCORD was to determine if intensive glycemic control, intensive lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness. The ACCORD trial failed to show a beneficial effect of intensive blood pressure or lipid therapy on the primary outcome, and intensive glycemia management actually increased mortality. The hypothesis underlying this ancillary study is that the failure of ACCORD to achieve its goal of reducing cardiovascular risk in diabetic patients through intensive management of hyperglycemia, dyslipidemia, and hypertension may be the result of variation in drug response due to genetic variation between individual participants. Benefits of intensive therapy may accrue to subsets of subjects with specific genetic variants predisposing to efficacious responses to particular therapeutic regimens, and harms may accrue to those with other variants predisposing to poor efficacy or adverse events. Identifying these variants could lead to a precision medicine approach to treating diabetes where each patient's genetic profile could identify the most efficacious treatment regimen with the lowest likelihood of adverse events. To test this hypothesis, a genome-wide genetic analysis was undertaken, incorporating both common variants distributed across the genome and rare variants targeted to exonic regions. Associations of genetic variants with short term responses to individual medicines as well as long term outcomes were investigated. The dataset is composed of genetic data from the ~6100 participants who agreed to participate in the ACCORD optional genetic studies and who allowed broad investigator access to their samples and the data derived from those samples, and from whom a DNA sample of sufficient quality was obtained. While a total of 8514 participants consented to the optional genetics studies, not all consented to broad investigator access, and those who did not are not included in this dataset, although they were also genotyped. Access to these additional genotypes can only be obtained by direct collaboration with the investigators of this study. Phenotype data used in the association analyses are derived from the ACCORD public release clinical data set, which has been made available through BioLINCC.

  Study phs001411

• Exploratory novel biomarker and resistance mechanism of milademetan, an MDM2 inhibitor, in MDM2 amplified intimal sarcoma from an open-label phase 1b/2 trial ���NCCH1806/MK004���

  Amplified Murine double minute 2 (MDM2) is found in > 70% of intimal sarcoma, known as one of the ultra-rare sarcomas. Milademetan (DS3032, RAIN-32) is a novel, specific, small-molecule MDM2 inhibitor that disrupts MDM2 and the tumor suppressor protein p53 interactions in tumor cells. We conducted a phase 1b/2 trial (Trial registration No: JMA-IIA00402) in patients with amplified MDM2 wild-type TP53 intimal sarcoma as a sub-study under the nationwide large registry for rare cancers in Japan (MASTERKEY Project). Eleven patients were enrolled, and ten were included in the efficacy analysis. Two (20%) patients had durable responses for > 15 months. Milademetan provided clinical benefits in patients with amplified MDM2 intimal sarcoma. Predictive biomarkers other than amplified MDM2 and acquired resistance mechanisms for milademetan are unknown. Whole-exome and RNA sequencing analyses of pre-treatment tissue samples were conducted to identify determinants of response. Genomic alterations were analyzed for 10 patients, and gene expression was analyzed for 9 patients using their pre-treatment tissue samples. Targeted sequencing of cell-free DNA (cfDNA) samples (liquid biopsy) was also conducted sequentially at three points [before treatment with milademetan (baseline), at Cycle 2 Day1, and at the time of disease progression] to identify determinants of response and resistance. From whole-exome and RNA sequencing analyses of pre-treatment tissue samples, we could not find any molecular pathways associated with the anti-tumor activity of milademetan. Focusing on 8 genes (CDK4, CDKN2A, CDKN2B, EGFR, ERBB3, MDM2, PDGFRA, TP53) known to be frequently affected in intimal sarcoma and 10 genes (AKT1, ATM, BBC3, CDKN1A, CDKN1C, CHEK2, MDM4, PMAIP1, PPM1D, TWIST1) reported to be associated with MDM2 inhibitor responses; we found that anti-tumor activity correlated with amplified TWIST1 (p-value = 0.028) and negatively with CDKN2A loss (p-value = 0.071). Eight of the 10 patients had their cfDNA collected sequentially at baseline, at Cycle 2 Day1 and disease progression; however, one did not consent to the exploratory analysis study using cfDNA, and one had cfDNA collected at baseline but not at disease progression due to ongoing treatment. Of the eight patients, TP53 mutations in cfDNA were detected in one and five patients at baseline and disease progression, respectively. The cfDNA allele frequency of TP53 mutations increased with disease progression. CDKN2A loss and amplified TWIST1 could be associated with the anti-tumor activity of milademetan in patients with MDM2 amplified intimal sarcoma. Acquired TP53 mutations were detected in sequential liquid biopsies as loss-of-function mutations, and these TP53 mutations might compromise the anti-tumor activity.

  Study JGAS000619

• Sanger sequencing of catalytic-domain encoding exons of tyrosine kinase genes from human endometrial tumor DNAs

  The purpose of the original study was to search for somatic mutations in the tyrosine kinome of serous and clear cell endometrial carcinomas (human). The study was conducted in two phases. Phase 1: A mutation discovery screen, in which ~577 exons encoding the catalytic domains of 86 tyrosine kinases were PCR-amplified and bidirectionally Sanger sequenced from 24 serous, 11 clear cell, and 5 mixed histology endometrial tumors. This was followed by alignment of sequence reads to the human reference sequence and subsequent nucleotide variant calling to identify potential somatic (tumor-specific) mutations. Potential somatic mutations were confirmed by re-amplification and sequencing of the relevant tumor DNA as well as matched non-tumor ("normal") DNA from the same case. Phase 2: A mutation prevalence screen, in which the non-catalytic regions two tyrosine kinase genes, TNK2 and DDR1, were PCR-amplified and sequenced from the 40 discovery screen tumors, and all coding exons of TNK2 and DDR1 were PCR-amplified and sequenced from another 10 clear cell, 21 serous, and 41 endometrioid endometrial tumors, in an effort to identify additional somatic mutations in each gene. Exons encoding the exonuclease domain of POLE were also sequenced to document somatic mutations.

  Study phs000841

• Joslin Study on the Genetics of Type 2 Diabetes

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

  Study phs002959

• NHLBI TOPMed: Recipient Epidemiology and Donor Evaluation Study-III Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  Establishing a Brazilian Sickle Cell Disease Cohort and Identifying Molecular Determinants of Response to Transfusions, Genetic Determinants of Alloimmunization, and Risk Factors Associated with HIV Infection. The REDS-III Brazil SCD Cohort study focused on transfusion practices and predictors of health outcomes in patients with Sickle Cell Disease (SCD) and began in the Fall of 2013. The four primary aims of this study are: 1) Aim A - Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; 2) Aim B - Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; 3) Aim C - Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; and, 4) Aim D - Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients. Patients are enrolled from six hospitals affiliated with the participating four REDS-III Brazil hemocenters.

  Study phs001468

• Characterizing Advanced Breast Cancer Heterogeneity and Treatment Resistance through Serial Biopsies and Comprehensive Analytics

  This dataset accompanies the manuscript "Characterizing Advanced Breast Cancer Heterogeneity and Treatment Resistance Through Serial Biopsies and Comprehensive Analytics". In this study we discuss the clinical implications and consequences of molecular heterogeneity in a metastatic breast cancer patient identified through serial biopsies, multi-omic analysis, and longitudinal patient monitoring, performed through the precision oncology program, Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART). This case study describes a metastatic breast cancer patient with a highly heterogenous tumor that began as ER positive/HER2 negative on diagnosis, then was found to be ER negative/HER2 positive in a metastatic liver lesion (Study biopsy #1), and finally triple negative (TNBC) in another metastatic liver biopsy (Study biopsy #2). Multi-omic assays included clinical genomic panel sequencing, clinical immunohistochemistry, a clinical protein profiling assay (Intracellular Signaling Protein Profiling), RNA sequencing, and RPPA. Here we provide the expression data from RNAseq and RPPA data on Study biopsy #2 for the patient discussed in this case report. Note: The first liver biopsy did not yield sufficient material for RNAseq or RPPA.Raw RNA FASTQ files from Study biopsy #2 of the liver Gene expression (RNAseq) files from Study biopsy #2Protein expression (RPPA) files (level 2, 3, 4) for Study biopsy #2

  Study phs002321

• Early Detection of Malignant and Pre-Malignant Peripheral Nerve Tumors Using Cell-Free DNA Fragmentomics

  Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

  Study phs003712

• Chronic Renal Insufficiency Cohort (CRIC) - GWAS

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. Data available at dbGaP include genotype data for 3527 participants released in version 1. Plasma metabolomics and plasma proteomics data will be available at dbGaP in "Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP. More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at http://cristudy.org/Chronic-Kidney-Disease/Chronic-Renal-Insufficiency-Cohort-Study/bibliography-2024-2023.

  Study phs000524

• CRUK-ICGC Prostate Cancer Group Study

  Prostate cancer somatic genomic sequencing data generated from 2011 onwards under auspices of the International Cancer Genome Consortium Prostate Cancer UK consortium (CRUK-ICGC Prostate Group), co-led by Colin Cooper and Ros Eeles, with other Principal Investigators (Brewer, Neal, Bova, McDermott, Wedge, Lynch, Massie, and Foster) and others as listed in study publications. Funded by Cancer Research UK and other funders as listed in study publications. Contents and publications related to each dataset are described with each dataset (EGAD) entry. Our study was funded with the ambition of collecting Whole Genome DNA sequence data from 250 prostate cancers, with matching transcriptome and methylome data. The original aims of the project were: 1.To understand the significance of multifocal prostate cancer. 2.To understand the clinical heterogeneity of prostate cancer to devise markers for predicting outcome and for drug targeting. 3.To understand the molecular basis of development and spread of castration-resistant and metastatic disease 4.To understand the aetiology of prostate cancer particularly the large variation in incidences that occur in different populations and ethnic groups. Please see https://doi.org/10.5281/zenodo.4022439 for links between sample IDs reported in literature and EGA IDs.

  Study EGAS00001000262

• Molecular determinants of response to PD-L1 blockade across tumor types

  Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity was observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC were molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A was identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis revealed molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.

  Study EGAS00001004343

• Whole Exome Sequencing PPGL

  Whole exome sequencing (WES) libraries were prepared with the SureSelectXT Human All Exon V6+COSMIC target enrichment system (Agilent, 5190-9307) by following kit manufacturer`s instructions. 200 ng of genomic DNA from FFPE tumoral samples and 1 µg from FF or germline samples were used as starting material. SureSelectXT HS (Agilent, G9704A) and SureSelectXT2 (Agilent, G9621A) reagent kits were alternatively used for FFPE derived and good quality samples, respectively. DNAs were fragmented on a Covaris S2 sharing instrument based on initial sample’s integrity. Fragmented DNA samples were processed through subsequent enzymatic treatments of end-repair, dA-tailing, and ligation to Illumina's adapters. Adapter-ligated libraries were PCR amplified with Illumina PE primers and subsequently hybridized to SureSelect Oligo Capture Library Mix. Biotinylated hybrids were captured and the enriched fraction eluted. Libraries were completed by limited-cycle PCR with Illumina TruSeq primers and KAPA HiFi HotStart DNA pol (Roche KK2501). Sample-specific libraries were combined into equimolarly balanced pools and applied to Illumina flow cells for cluster generation. Sequencing was performed on either the Illumina HiSeq2500 or NovaSeq6000 in a paired-end 100bp reads mode to a median target coverage of ~200x and ~100x for tumors and germline, respectively.

  Study EGAS00001006043

• Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

  Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of multiple sclerosis (MS) patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell compartments and observed clonally related cells of different isotypes, including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in antibody-secreting cells, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes.

  Study EGAS00001005745

• Pooled scRNA-seq of iPSC-derived neural stem cells from ADHD and control individuals

  This dataset comprises paired-end FASTQ files from single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed from somatic cells (keratinocytes, PBMCs, or lymphoblastoid cell lines) collected from individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) and age-matched healthy controls (ages 6–18 years). Reprogramming was carried out using the non-integrative Sendai virus system (CytoTune-iPS 2.0, Thermo Fisher Scientific), introducing OCT3/4, SOX2, KLF4, and cMYC. iPSCs were cultured in Essential 8 medium on vitronectin and underwent rigorous quality control including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping (Illumina Global Screening Array). NSCs were generated using a standardized neural induction protocol and validated via qRT-PCR and immunostaining for markers including PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Two independent scRNA-seq multiplexed experiments were performed: Experiment 1 (ADHD: n = 7; Control: n = 6) and Experiment 2 (ADHD: n = 9; Control: n = 7). Samples were pooled and demultiplexed using the Ensemblex algorithm, incorporating prior genotype data. After quality control filtering (>500 unique RNA molecules per cell), 30,433 single-cell transcriptomes were retained. Differential gene expression analysis was conducted to identify transcriptional signatures associated with ADHD compared to controls.

  Study EGAS00001008169

• snRNA-seq analysis in multinucleated myogenic FSHD cells identifies heterogeneous FSHD transcriptome signatures associated with embryonic-like program activation and oxidative stress-induced apoptosis

  The sporadic nature of DUX4 expression in FSHD muscle challenges comparative transcriptome analyses between FSHD and control samples. A variety of DUX4 and FSHD-associated transcriptional changes have been identified, but bulk RNA-seq strategies prohibit comprehensive analysis of their spatiotemporal relation, interdependence and role in the disease process. In this study, we used single-nucleus RNA-sequencing of nuclei isolated from patient- and control-derived multinucleated primary myotubes to investigate the cellular heterogeneity in FSHD. Taking advantage of the increased resolution in snRNA-sequencing of fully differentiated myotubes, two distinct populations of DUX4-affected nuclei could be defined by their transcriptional profiles. Our data provides insights into the differences between these two populations and suggests heterogeneity in two well-known FSHD-associated transcriptional aberrations: increased oxidative stress and inhibition of myogenic differentiation. Additionally, we provide evidence that DUX4-affected nuclei share transcriptome features with early embryonic cells beyond the well-described cleavage stage, progressing into the 8-cell and blastocyst stages. Altogether, our data suggests that the FSHD transcriptional profile is defined by a mixture of individual and sometimes mutually exclusive DUX4-induced responses and cellular state-dependent downstream effects.

  Study EGAS00001007635

• The Role of CTCF in the Organization of the Centromeric 11p15 Imprinted Domain Interactome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder and comprises a spectrum of overgrowth phenotypes. While approximately 35% of BWS cases are caused by isolated loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15, only around 5% of patients develop BWS due to structural alterations to the IC2 domain. In this study, we identify a BWS-causing 7.6 kB familial deletion within the IC2 domain by performing Whole Genome Sequencing (WGS) on patient-derived human fibroblasts. Using a chromatin conformation capture technique, Capture C, on 3 control fibroblast samples, 3 BWS LOM fibroblast samples, and the single familial deletion sample, we investigate how the domain interactome changes in BWS patients. We find that high-strength interactions occur within the IC2 domain between the 5’ end of KCNQ1, KCNQ1 intron 2, and the 5’ end of CDKN1C in the control profile that are largely abrogated in the BWS samples, but some lower frequency contacts between the imprinting control region (ICR), KCNQ1 intron 2, and the 5’ end of CDKN1C are unaffected. We conclude that the strong KCNQ1-CDKN1C interactions are important in maintaining the domain imprint.

  Study phs002408

• Analysis of the Whole Transcriptomes of Human Testis with Complete Spermatogenesis and of Human Testes with Sertoli Cell-Only Syndrome

  Sertoli cell-only syndrome is severe form of human male infertility in which most seminiferous tubules appear to lack all spermatogenic cells, including spermatogonial stem cells (SSCs). However, a few small tubule segments of some patients have active spermatogenesis and, thus, functional stem cell niches and SSCs. Normally SSCs replicate, migrate and refill adjacent empty niches, but this does not appear to occur in SCO syndrome. We hypothesized that this failure occurs because most niches are dysfunctional. As Sertoli cells are essential to formation of these niches, we used RNAseq to compare the transcriptomes of human testes with qualitatively normal (complete) spermatogenesis (n=4) with the transcriptomes of human testes with SCO syndrome (n=7). We then focused our analysis on the expression of transcripts that bioinformatic analyses identified as Sertoli cell signature transcripts. Results show that Sertoli cells in SCO testes express abnormally low levels of GDNF, FGF8 and BMP4, all of which are important regulators of mouse SSCs and/or progenitor spermatogonia. Sertoli cells in SCO testes express significantly reduced levels of transcripts for proteins that polarize the Sertoli cell plasma membrane and regulate the trafficking of cell adhesion and gap junction proteins in and out of that plasma membrane.

  Study phs001777

• The National Heart, Lung, and Blood Institute (NHLBI)-funded Next Generation Genetic Association Studies (NextGen) Consortium: Phenotyping Lipid traits in iPS derived hepatocytes Study (PhLiPS Study)

  The goal of the PhLiPS study is to create a library of induced pluripotent stem cell (iPSC) lines and iPSC-derived hepatocytes of diverse genotypes for use in metabolic profiling and interrogating lipid phenotypes. These cell lines were created as a part of the Next Generation Genetic Association Studies (Next Gen) Program, which was a five-year, $80 million program to investigate functional genetic variation in humans by assessing cellular profiles that are surrogates for disease phenotypes. To achieve this, researchers from multiple institutions across the U.S. were awarded grants to derive iPSC lines from more than 1,500 individuals representing various conditions as well as healthy controls for use in functional genomic ("disease in a dish") research. This extensive panel includes a diverse set of age, gender, and ethnic backgrounds, and therefore will be an invaluable tool for evaluations across demographics. Further enhancing the utility of these cell lines are data sets such as phenotyping, GWAS, genome sequencing, gene expression and -omics analyses (e.g., lipidomic, proteomic, methylomic) that can be matched to the cell lines. The PhLiPS Study focuses on individuals free of cardiovascular disease or with lipoprotein metabolism disorders in the community served by the Hospital of the University of Pennsylvania.

  Study phs001341

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Emory Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort selected from Emory University Cardiovascular Biobank. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. For these samples "early age" is defined as men 60 years of age or younger and women 70 years of age or younger. The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases.

  Study phs001880

• CPTAC: Proteogenomic Studies of Ovarian Tumor Responses to Agents Targeting the DNA Damage Response

  There is a critical unmet need for predictors of chemo-refractory High-grade serous ovarian cancer (HGSOC). Despite over 3 decades of research on platinum responses in cancer, no predictive biomarker has been translated into clinical use. Predictors of refractory disease could spare these patients the unnecessary toxicity of a platinum-based regimen and provide a means to triage these patients to clinical trials to identify effective therapies for refractory disease. This study has approached the development of a predictor in a novel way enabling detection of a multi-analyte panel biomarker capable of detecting a subset of refractory HGSOCs with high specificity and implicating potential treatment vulnerabilities for refractory disease. We reported the first proteogenomic analysis of platinum refractoriness in HGSOC and made the novel dataset available as a resource to the community, including a ProTrack portal: http://ptrc.cptac-data-view.org/. Detailed proteogenomic profiles were generated for this study from a retrospective cohort of 242 treatment-naive HGSOCs with enriched representation of "exceptional non-responders" (i.e., patients with chemo-refractory disease). Whole genome sequence (WGS) and RNA seq FASTQ files are available through dbGaP. Proteomic data are available through the NCI Proteomic Data Commons (PDC): https://pdc.cancer.gov/pdc/.

  Study phs003152

• Whole Genome Profiling to Detect Schizophrenia Methylation Markers

  Schizophrenia (SCZ) is a devastating psychiatric disorder. The aim of this study was to detect DNA methylation (5meC) profiles in whole blood associated with SCZ. The sample consisted of schizophrenia cases and controls selected from national population registers in Sweden. We employed MBD protein-based enrichment of the methylated DNA fraction, followed by single end sequencing (50 bp reads) on the SOLiD platform. To improve methylome-wide coverage we used an existing protocol variant, which increases the relative number of fragments from CpG poor regions. To analyze the data, we used an analysis pipeline described elsewhere7, that was designed specifically for MBD-seq and included alignment, quality control (QC) of reads and samples, coverage calculations for the 26,752,702 autosomal CpGs in the reference genome using a non-parametric estimate of the fragment size distribution, an in silico experiment to identify CpGs in loci with alignment problems, a 2-stage adaptive algorithm to combine data from correlated adjacent CpG sites in "blocks", principal component analysis (PCA), association testing, bioinformatics annotation and network analysis. After QC, 1459 subjects with on average 32.4 million high quality reads remained. Association testing was performed on 4.3 million high quality blocks after regressing out possible assay related technical artifacts, sex/age, and unmeasured confounders through the PCA components.

  Study phs000608

• CIP: Obesity-Diabetes Familial Risk, Viva La Familia Study

  The VIVA LA FAMILIA Study was designed to identify genetic variants influencing childhood obesity and its comorbidities in the Hispanic population. Family recruitment and phenotyping were conducted in 2000-2005 in Houston, TX. All enrolled children (n=1030) and parents gave written informed consent or assent. The protocol was approved by the Institutional Review Boards for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals and for Texas Biomedical Research Institute. The VIVA LA FAMILIA study design and methodology have been described in detail (Butte NF, 2006). Each family was ascertained on an obese proband, defined as a BMI > 95th percentile, between the ages 4-19 y. The cross-sectional, longitudinal study design consisted of baseline measurements, with a one-year. GWAS was performed using the Illumina HumanOmni1 v1.0 BeadChips on 815 children from 263 Hispanic families and HumanOmni 2.5-8v1 on an additional 43 children. Exome sequencing is being performed on 822 children using NimbleGen capture, followed by Illumina DNA sequencing. Butte NF, Cai G, Cole SA, Comuzzie AG. Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in Hispanic population. Am J Clin Nutr 2006;84(3):646-54. PMID: 16960181

  Study phs000616