Search Results - EGA European Genome-phenome Archive

Genomic Profiling of Rare Tumors

Utilizing the rare and unique patient samples provided by Pattern Medicine, LLC, MD Anderson will molecularly characterize rare cancer samples, and potentially generate a collection of preclinical models to enable identification of novel therapeutic targets and concepts, as well as evaluation of innovative treatment strategies.

Study phs003916

Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program –Sarcoma, Kidney, and Liver Cancers

The goal was to complete whole exome sequencing (WES) and RNA sequencing (RNA-Seq) on patient derived xenograft samples. Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be 'cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds 80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our group has contributed to studies in the Pediatric Preclinical Testing Program (PPTP) and Pediatric Preclinical Testing Consortium (PPTC) that have led to clinical studies through Children's Oncology Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX), developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act).

Study phs003160

NCTN: Phase III Randomized Study of Sorafenib Plus Doxorubicin versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) (CALGB-80802)

Study ID: CALGB-80802NCT Number: NCT01015833 Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Phase III Randomized Study of Sorafenib plus Doxorubicin versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) (CALGB-80802)Trial Description: This randomized phase III trial studies sorafenib tosylate and doxorubicin hydrochloride to see how well they work compared with sorafenib tosylate alone in treating patients with liver cancer that has spread to nearby tissue or lymph nodes or has spread to other places in the body. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving sorafenib tosylate together with doxorubicin hydrochloride is more effective than sorafenib tosylate alone in treating liver cancer. Data presented in the following publication(s): PMID 31486832 Disease type(s): Gastrointestinal Neoplasm - Liver and Hepatobiliary CancerClinical Dataset(s) included:NCT01015833-D1 (PMID 31486832): Dataset NCT01015833-D1 is the only dataset associated with PubMed ID 31486832. This dataset contains baseline characteristics, treatment arm and number of cycles, treatment discontinuation reasons, hepatitis status, toxicity, and survival data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004239

Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

Study phs003641

Integrating Circulating Tumor DNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer

DNA was isolated from pre-treatment and mid-treatment plasma samples and matched germline samples from patients undergoing chemoradiation therapy for stage IIB-IIIB non-small cell lung cancer. Sequencing libraries were hybrid captured using custom selector pools designed to target genes frequently mutated in non-small cell lung cancer prior to ultra-deep next generation sequencing.

Study phs003947

Dynamic Evolution of Fibroblasts Revealed by Single Cell RNA Sequencing of Human Pancreatic Cancer

Understanding the constituents of the pancreatic ductal adenocarcinoma (PDAC) microenvironment may illuminate more efficacious targets for treating this aggressive malignancy. However, the compositional changes occurring in untreated and treated PDAC relative to both normal and inflamed pancreas have not been well characterized. To provide a more comprehensive understanding of the PDAC tumor microenvironment relative to the non-cancerous pancreas, we performed single-cell expression profiling (10X Genomics Chromium) on samples of upfront resectable PDAC, FOLFIRINOX-based treated PDAC, chronic pancreatitis, and normal pancreas specimens from 19 patients. Spatial gene expression profiling (10X Genomics Visium) was performed to gain additional insight into cell populations. Our analysis revealed that fibroblasts are central mediators of cell-cell communication in both inflamed and malignant settings and defined unique roles for these cell populations in different disease contexts.

Study phs003751

Blood and Marrow Transplant Clinical Trials Network - A Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell/Myeloma Fusions (BMT CTN-1401-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 compare response at one year post transplant between participants receiving dendritic cell/myeloma vaccine along with granulocyte macrophage colony-stimulating factor (GM-CSF) and lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF.Background: The advent of combination biologic therapy for multiple myeloma (MM) has significantly improved patient outcomes. Induction therapy followed by consolidation with autologous hematopoietic stem cell transplantation (auto-HCT) prolongs progression-free survival in patients with MM. The addition of post-transplant lenalidomide maintenance therapy further extends the duration of remission. However, the vast majority of patients ultimately experience disease progression due to the emergence of resistant disease. The development of strategies to enhance the durability of post-transplant response remains a major unmet need in the field. Since MM is associated with immune suppression, the development of cancer vaccines is being investigated in MM with the goal of stimulating tumor-specific immunity. Dendritic cells (DC) are the most potent antigen-presenting cells that prominently express costimulatory signaling necessary for optimal T-cell activation, cross-presentation of antigen to reactive CD8 T cells, and the development of primary immunity. The BMT CTN developed a personalized cancer vaccine in which patient-derived tumor cells are fused with autologous monocyte-derived DCs. The BMT CTN-1401 study examined the efficacy of the DC/MM fusion vaccine in conjunction with lenalidomide maintenance therapy after auto-HCT, compared with maintenance alone.Participants: Participants with symptomatic MM were eligible if they were 18-70 years old, were candidates for auto-HCT, had a Karnofsky Performance status of ≥70%, had >20% plasma cells in the bone marrow aspirate differential A total of 140 participants were randomized. 68 participants were randomized to the vaccine arm, 37 to the lenalidomide plus GM-CSF arm, and 35 to the lenalidomide alone arm.Design: BMT CTN-1401 was a phase II, multicenter, open label trial. All participants underwent bone marrow aspiration following enrollment. Myeloma cells were isolated, preserved, and for participants randomized to the vaccine arm, used for vaccine generation. All participants received standard-of-care induction therapy and auto-HCT conditioned with melphalan. Participants were randomized approximately 2 months post-transplant. Participants were randomized in a 2:1:1 ratio to the vaccine arm (DC/MM vaccine, GM-CSF, plus lenalidomide), or one of two control arms (lenalidomide plus GM-CSF or lenalidomide alone). All participants began maintenance lenalidomide between day 90 and 100 post-transplant at a dose of 10 mg a day for 28 days of a 28-day cycle. On day 1 of cycles 2, 3, and 4 of lenalidomide maintenance, patients assigned to the vaccine arm underwent subcutaneous administration of the DC/MM fusion vaccine along with 100 μg GM-CSF administered subcutaneously adjacent to the vaccine site on days 1 to 4. Participants randomized to the control arms received either lenalidomide alone or lenalidomide with GM-CSF at the same dose and schedule as the vaccine arm.The primary outcome was a comparison of participants in complete response (CR)/stringent CR (sCR) at 1-year post-transplant between the vaccine and control arms. The primary immunologic endpoint of the study was a comparison of the percentage of circulating multiple myeloma–reactive T cells between participants in the vaccine and control arms. PFS (progression-free survival) and OS (overall survival) were secondary endpoints of the study.Conclusions: There was not a statistically significant difference in the percentage of participants achieving complete response 1-year post-transplant in the vaccine arm compared to the control arms.

Study phs004718

NCTN: Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer (E5204)

Study ID: E5204NCT Number: NCT00303628 ECOG-ACRIN Cancer Research GroupSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil, Leucovorin and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Pre-operative Chemoradiation (E5204)Trial Description: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating rectal cancer. This randomized phase III trial is studying combination chemotherapy to see how well it works with or without bevacizumab in treating patients who have had surgery for stage II or stage III rectal cancer. Clinical data presented in the following publication(s):PMID 31852811 Disease type(s): Gastrointestinal Neoplasm - Colorectal CancerClinical dataset(s) included:NCT00303628-D1 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D1, contains baseline characteristics, stratification factors, surgery information, treatment, second primary cancer and efficacy data. NCT00303628-D2 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D2, contains toxicity data. NCT00303628-D3 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D3, contains PRO Bowel function/uniscale data. NCT00303628-D4 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D4, contains PRO FACT-Diarrhea Data. NCT00303628-D5 (PMID 31852811): There are five different datasets for PMID 31852811 from trial E5204. This dataset, NCT00303628-D5, contains PRO FACT/GOG-Ntx Data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004621

Establishment and Genomic Validation of Novel Patient-Derived Xenograft Models for Drug Discovery in Gastrointestinal Stromal Tumor

This dataset contains targeted next-generation sequencing data generated with the Illumina TruSight Oncology 500 (TSO500) assay from six gastrointestinal stromal tumors (GIST) and matched patient-derived xenograft (PDX) models established at Fox Chase Cancer Center (Philadelphia, PA). GIST are most commonly driven by activating mutations in KIT or PDGFRA, and this study focused on KIT-mutant tumors. All PDXs were derived from metastatic patient tumors previously treated with one or more tyrosine kinase inhibitors (TKIs). PDXs were maintained through series of passages and represents in vivo models of differential TKI sensitivity. The dataset represents a detailed comparison of mutational profiles between primary tumors and corresponding PDXs across passages, enabling studies of genomic stability, resistance mechanisms, and the evaluation of novel therapeutic strategies in GIST.

Study phs004185

The Electronic Medical Records and GEnomics Network Genomic Risk Assessment (eMERGE IV)

The eMERGE (electronic MEdical Records and GEnomics) network enrolled ~25,000 individuals not typically involved in research in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report along with recommended actions. The GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports and was returned to participants, their providers, and their EHR. The network is examining the uptake of care recommendations after return of results.Children's Hospital of Philadelphia (CHOP)The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP) with the primary goal of translating basic research findings to medical innovations. The mission of CAG is to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders. We aim to discover genetic causes for the most prevalent diseases of childhood including ADHD, asthma, autism, diabetes, epilepsy, obesity, schizophrenia, pediatric cancer, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Our participants are recruited from the CHOP Health Care Network, which includes over 50 sites throughout Pennsylvania and New Jersey, 100% of which use Epic EMR system. This constitutes the country's largest pediatric integrated delivery system, supporting >1.1 million visits/year within the primary and specialty care networks, community-based inpatient pediatric and neonatal programs, a rehabilitation hospital, and a home care service. It provides acute- and well-care to patients in urban, rural, and suburban settings.Cincinnati Children's Hospital Medical Center (CCHMC)CCHMC has proposed ambitious initiatives for eMERGE IV. The major goals are to generate, return as appropriate along with clinical recommendations, individualized genomic risk assessments that include polygenic risk scores for 2500 minority participants ascertained on dyads (mother/child) and extended to families (dyad + biologic father, siblings). The informatics initiatives include integration of electronic medical records and development, implementation and evaluation of clinical decision support at two different hospital systems, one pediatric and one adult. Participant preferences, education needs, and ethical and social implications will be studied throughout the 5 year period. Columbia UniversityColumbia University in partnership with the New York-Presbyterian hospital has a long and strong tradition of patient-centered research and community engagement in the urban, medically underserved communities of Washington Heights and Harlem in Northern Manhattan, and has established Precision Medicine as a major university-wide initiative (PMI), of which eMERGE is a vital program. We possess broad and deep expertise in clinical genetics, genomics, informatics, EHR phenotyping, systems biology, public health, and ELSI, including return of genetic results and secondary findings to diverse patients. Columbia will share lessons learned in linking EHR and sequence data for genomic decision support, developing scalable genomic education methods and assessing the impact of returning genetic results on patients, families, and clinicians. We are poised to contribute novel comprehensive risk prediction and management solutions for diverse patients as part of eMERGE IV efforts.Icahn School of Medicine at Mt. Sinai (Mt. Sinai)Mt. Sinai investigators have been at the center of many NHGRI-led genomic research (GSP, PAGE) and genomic medicine (eMERGE, CSER, IGNITE) consortia. Building on our decade-long track record in genomic research, clinical trials, and genomic medicine in diverse, underserved patients from New York City, we propose to develop new frameworks to bring genomic risk into clinical care to promote health equity. In addition to genomic discovery and risk prediction, we are creating analytical and data resources, and digital health applications tailored to diverse populations, as part of the eMERGE IV Network. The Mt. Sinai team is composed of clinicians and scientists who work closely with community members and industry partners to develop flexible and innovative strategies to bring leading-edge research into clinical care. Having recently announced a large institutional investment to scale the integration of genomics and artificial intelligence into patient care, Mt. Sinai is poised to contribute to eMERGE IV's mission to implement and learn from genomic risk assessment in clinical care. Mt. Sinai's team will contribute to progress in multiple areas across eMERGE, including developing and deploying electronic phenotypes; discovering new genotype-phenotype associations; and facilitating the communication of genomic results to patients and their healthcare providers.Mass General BrighamThe eMERGE IV Clinical Center at Mass General Brigham leverages a large biobank, clinical data in the electronic health records (EHR) for >6 million patients from the largest integrated health care provider in New England, advanced bioinformatics expertise, prior leadership in PRS development, established expertise in returning genomics results, and experience using information technology to transform clinical processes and assess medical, behavioral and economic outcomes. We have developed highly specific machine learning algorithms for e-phenotypes and implemented eMERGE algorithms for multiple phenotypes and have considerable experience in developing decision support tools and analyzing outcomes that can be leveraged to study the integration of PRS data into clinical practice. We will test the hypothesis that PRS will allow us to stratify eMERGE participants based on genetic risk for common complex traits. We will focus on coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer and depression in GWAS populations and validate multi-ethnic PRS in the Mass General Brigham Biobank and eMERGE III dataset. We will conduct an analysis of the effect of disclosing results to high risk participants to determine how personalized results changed patient outcomes in laboratory values, risk reduction behaviors, or health care utilization.Mayo Clinic (Mayo)The goal of Mayo eMERGE investigators is to leverage the electronic health record (EHR) for genomic discovery and to implement genomic medicine to improve health care outcomes, working closely with other eMERGE sites and the Mayo Center for Individualized Medicine. In eMERGE I we used genotype data and electronic phenotyping algorithms for genomic discovery. In eMERGE II we conducted a clinical trial of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD) and placed pharmacogenomic variants in the EHR with linkage to clinical decision support (CDS). In eMERGE III, we returned actionable findings from targeted sequencing of 68 genes and collaborated with a Federally Qualified Health Center (FQHC) to bring genomic medicine to an under-represented population. In eMERGE IV, as part of the Genomic Risk Assessment & Management Network, we will test the hypothesis that individuals at high polygenic risk for common diseases will have a higher uptake of risk reduction measures than those at lower risk. We will build on our prior work in genomic discovery, EHR integration and return of results (RoR) to develop and validate PRS and combine these with clinical risk scores and family history to compute comprehensive risk profiles for 2500 individuals. Our prior work in disclosing a PRS for CHD to research participants as part of a comprehensive risk profile enables us to efficiently expand the approach to other common diseases that pose a significant public health burden. To assess the utility of PRSs, we will recruit 1800 adults and 200 adolescents from Rochester MN and 500 adults from Phoenix AZ. DNA will be sent for CLIA-certified genomic testing and we will calculate ancestry specific PRSs for each participant. Individualized risk estimates will be reported to participants and health care providers (HCPs) and placed in the EHR with linkage to CDS that includes guideline-based risk-management information. For participants who are at significantly higher polygenic risk of developing at least 1 of the diseases, results will be disclosed in-person by a HCP followed by assessment of outcomes including new tests ordered, risk reduction measures, and changes in modifiable risk factors. We will examine the economic, behavioral and psychosocial implications of returning PRS. Our focus on PRS for common cardiovascular diseases brings genomic medicine to the population. We will continue our partnership with Mountain Park Health Center, a FQHC serving low-income, minority communities in Phoenix AZ, to address concerns about health disparities in the context of genomic medicine.Northwestern University (NU)Northwestern University is dedicated to translational genomics, with a strong focus on unified, interdisciplinary research bridging the informatics, clinical, basic science, and bioethics domains. Over the phases of eMERGE, Northwestern has applied this interdisciplinary approach to study the feasibility, utility, outcomes, and effectiveness of EHR-linked genomic information as a member of the network. Particular areas of focus include: novel informatics approaches to integrate genomic results into EHR systems; development of open-source, EHR-based phenotyping algorithms to empower translational research across a variety of clinical domains; and studies of participant, patient, and provider interaction with EHR-based genomic results. In phase IV of eMERGE, Northwestern is building on this expertise to develop, deploy, and evaluate systems of EHR-based, genomics-guided clinical risk assessment and management tools across a variety of common, impactful conditions. Northwestern's cross-disciplinary approach to this work is empowered by an innovative smartphone app to consolidate outreach, enrollment, engagement, return of results, and dissemination of health education materials surrounding genetic risk and risk management. Focusing recruitment on community-based clinics, Northwestern aims to engage participants from communities that, though not traditionally included in academic research settings, could benefit significantly from these risk management approaches. By combining expertise in informatics and EHR integration with innovative return-of-results strategies rooted in behavior theory, Northwestern aims to provide valuable data on accuracy, utility, and uptake of genetic risk assessment as the field moves towards integrating genetic risk scores into clinical practice.University of Alabama at Birmingham (UAB)Our eMERGE team aims to bring our experience and expertise in research with medically underserved (>75%) populations to identify genomic signatures of common diseases, conduct genomic risk assessments within the clinical workflow and where appropriate, pre-treat at-risk patients with common diseases including diabetes, chronic obstructive pulmonary disease, obesity, coronary artery disease and prostate cancer. Our aims will also allow us to develop genomic risk assessments, and address challenges involved in bringing genomic medicine into routine medical care. Working with the eMERGE network, we will select the eleven diseases of public health impact and select polygenic risk scores for clinical implementation. We will conduct an ethical legal social implications (ELSI) study, to explore patient perspectives on the use of family history and polygenic risk scores for estimating disease risk among Alabama Genomic Health Initiative (a statewide cohort) participants. The results will inform the development of consent, educational materials, and a communication strategy to enhance recruitment and retention of eMERGE participants. Recruiting over 75% of patients from medically underserved communities, we will incorporate genomic risk, family history, and clinical data to identify high-risk patients, recommending risk reduction recommendations in concordance with practice guidelines. For high-risk patients, we will deploy clinical decision support and present the genomic risk assessments and risk reduction recommendations. We will assess three outcomes: uptake of recommendations (implementation outcome), adherence to clinic visits (engagement outcome), and surrogates of disease/control (clinical outcome; e.g. blood sugar, cholesterol). We bring our expertise and experience to collaborate with the eMERGE investigative team to leverage the power of genomics to prevent disease.University of Washington (UW)The eMERGE IV Northwest partnership includes clinicians, scientists, and professionals in other fields from University of Washington (UW) Medicine, UW Health Sciences, the Fred Hutchinson Cancer Research Center, and the Brotman Baty Institute for Precision Medicine. The eMERGE IV Northwest partnership aims to evaluate the use of genomic information in the health care of diverse participants at the University of UW. Our site is expected to lead work on the prediction of colon cancer, glaucoma, and cardiovascular disease; other conditions expected to be studied include diabetes, liver disease, high cholesterol, and osteoporosis. Working with our eMERGE colleagues, we will aggregate, into a single score that informs about the risk of a disease, a participant's polygenic test information, which looks at variants from across the genome, as well as other known risk factors, such as personal and family medical history, environmental and social determinants, and physical and lab results. This score would let clinicians know which patients might benefit from screenings or other interventions to reduce the risk of disease or make an early diagnosis. In addition to experts specializing in each of the medical conditions that are the focus of the Northwest site, leaders in health economics, and in the ethical and societal aspects of genomics and health care will also be part of the research team. Medical, as well as economic, outcomes will be measured. Stakeholder engagement will be encouraged to obtain comments from participants and their families.Vanderbilt University Medical Center (VUMC)Vanderbilt University Medical Center has embraced Personalized Health and Healthcare as a key pillar of our Research Strategic Plan. This institutional commitment has taken multiple forms including the development of key infrastructure resources (the institutional Biobank (BioVU); the program in preemptive pharmacogenetic testing; the genotyping and sequencing core) and support of faculty in key disciplines such as genomics, informatics, ethics, privacy science, and clinical pharmacology. VUMC's team has contributed importantly to progress in multiple areas across eMERGE, including developing and deploying phenotype algorithms; developing and managing the genotype quality control pipeline for the network (eMERGE I); discovering new genotype-phenotype relations in VUMC and cross-network datasets; actively participating in the PGx clinical implementation project, community consultation, and return of results initiatives; developing methods to resolve tensions between data access and individual privacy; developing sampling methodology for the CERC survey; and developing new software tools for the field, including for developing and validating phenotypes, de-identification and for the phenome-wide association study paradigm (“PheWAS”)eMERGE Network Coordinating Center (CC)Vanderbilt University Medical Center has been the coordinating center of the eMERGE Network since inception. During this phase of eMERGE we have partnered with the Broad Institute to to add expertise in large-scale genotyping, cloud computing, and genomic data analysis and management, and with Duke University to leverage its proficiency in the implementation of patient-oriented family history tools and delivery of risk assessments. To meet the needs of the Network, the CC continues to serve NHGRI, the Network, and its members in all coordination, communication, and collaboration functions while providing a nationally visible home for eMERGE authored tools and scientific productivity. The CC is also assisting the Network with selecting and validating polygenic risk scores (PRS) for approximately eleven complex diseases and developing genomic risk assessments (GRAs) which combine the PRS with other clinical risks, family history, and monogenic risks. Finally, The CC will coordinate a prospective study for 25,000 participants which calculates clinical and genomic risks for participants and their providers. In addition to providing the genotyping and PRS reporting services, we will develop with the Network scalable EHR-based methods to assess uptake of risk-reduction recommendations and clinical impact.

Study phs003905

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined with Nivolumab and Ipilimumab for Patients with Resected MMR-p Colorectal and Pancreatic Cancer

Phase 1 study for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic colorectal cancer who have exposure to 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab.

Study phs003425

Genomic Landscape and Preclinical Therapeutic Insights Developed from Xenograft, Organoid, and Cell Line Models in the NCI's Patient-Derived Models Repository

Patient-derived xenografts (PDXs), organoids (PDOrgs), and two-dimensional cell cultures (PDCs) are powerful tools for translational cancer research. The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR) features preclinical models from primary and metastatic lesions across a broad array of solid tumors, including rare and pediatric cancers, each annotated with genomic data as well as clinical information about the patient from whom the model originated (https://pdmr.cancer.gov). We used these models to demonstrate stable propagation of genomic aberrations over multiple passages, to evaluate patient-specific tumor heterogeneity, and to examine the relationship of the preclinical activity of a panel of approved and investigational anticancer agents in PDXs and PDOrgs to known levels of therapeutic activity in the clinic.

Study phs003984

Comprehensive Genomic Data Deposition for Pancreatic Cancer Precision Medicine Studies: Clinical Trials NCT02451982 and NCT02648282

This submission includes specimens from 89 pancreatic cancer patients at Johns Hopkins Hospital, comprising 41 surgically resectable and 48 locally advanced pancreatic cancer (LAPC) cases. These samples originate from two clinical studies, NCT02451982 and NCT02648282, following the Johns Hopkins Medical Institution Institutional Review Board-approved registry protocol at the Pancreatic Cancer Precision Medicine Center of Excellence Program. Written consent for specimen use, obtained from participants in the original studies, covers additional research, including this one. Biopsy specimens collected through endoscopic ultrasound-guided fine needle core biopsies or surgically resected tumors are included. NCT02451982 is a platform trial evaluating immunotherapy combinations for surgically resectable pancreatic ductal adenocarcinoma in the neo-adjuvant and adjuvant settings. It investigates the GVAX pancreatic cancer vaccine with immune-boosting cyclophosphamide, exploring immune cell trafficking and the impact of PD-1 blocking. NCT02648282 focuses on the efficacy and safety of combining cyclophosphamide, pembrolizumab, GVAX, and stereotactic body radiotherapy (SBRT) in locally advanced pancreatic cancer, with an emphasis on anti-tumor activity. Both studies provide valuable insights into innovative pancreatic cancer treatment approaches.

Study phs003600

NCTN: A Non-Randomized Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed High Risk Hodgkin Lymphoma (AHOD0831)

Study ID: AHOD0831NCT Number: NCT01026220Children's Oncology Group (COG)Submitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Non-Randomized Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed High Risk Hodgkin Lymphoma (AHOD0831)Trial Description: This phase III trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed Hodgkin lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells. Clinical data presented in the following publication(s):PMID 31180135Disease type(s): Hematopoietic Neoplasm/Lymphoma - Hodgkin LymphomaClinical Dataset(s) included:NCT01026220-D1 (PMID 31180135): There is one dataset for AHOD0831's primary publication 31180135. This dataset contains patient demographics, baseline characteristics, PET results, and survival endpoints. This dataset is presented at patient level and includes one record per patient.You are encouraged to view the PDF data dictionaries found in the "Documents" tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004161

Multi-Modal Single-Cell, Spatial, and Genomic Analyses of Human Non-Small Cell Lung Cancer Brain Metastases

We performed single nuclei RNA-sequencing (snRNA-seq) with matched T cell receptor sequencing (TCR-seq), and pool matched low pass whole genome sequencing (WGS) of 12 treatment-naive non-small cell lung cancer (NSCLC) primary tumors (PTs) and 31 treatment-naive NSCLC brain metastases (BMs). In total, we recovered 277,206 cell transcriptomes in 43 samples. Single-nuclei suspension from frozen NSCLC metastases were generated using methods published in Slyper et al. (Nature Medicine, 2020, PMID:32405060) with modifications. The tissue was first cut in 20 µm sections using a cryostat and stored on dry ice until the next step. Then the tissue was put on wet ice and washed once with 5 ml PBS to remove OCT. After this step nuclei were extracted by vigorous pipetting in salt-tris buffer with Tween-20 (TST) followed by a high-volume wash in salt-tris buffer (ST). Nuclei were counted and 10,000-14,000 and were loaded using a Chromium controller (10X genomics) and Chromium Single Cell 5' Reagents (V1.1 and V2). Complementary DNA libraries were generated according to manufacturer's instructions, with the modification of one additional cycle of amplification. Matched single nuclei T cell receptor (snTCR) sequencing libraries were prepared from amplified cDNA libraries using either Chromium Single Cell V(D)J Enrichment Kit for human T cells Reagent Kit, v1.1, or single cell human TCR amplification kit. Final snTCR sequencing libraries were prepared using Single Index Kit T Set A for V1.1 libraries or Library construction kit and Dual Index Kit TT set A for V2 libraries. Sequencing libraries were quantified using Tapestation D5000 reagents and a 2200 TapeStation and pooled for sequencing. Pool matched low pass whole-genome sequencing (lp-WGS) was performed in addition to snRNA-seq to improve the identification of the malignant and non-malignant cell compartments. Nuclei from snRNA-seq sample preparations were collected by centrifugation (500g, 5 min), snap frozen after removing excess ST buffer, and stored at -200C until further processing. If insufficient nuclei (0C for 9 minutes. Adapters were not diluted, and the optional PCR (5 cycles) and cleanup were performed. After library cleanup with AMPure beads (Beckman Coulter, Brea, CA), libraries were quantified with Tapestation D5000 HS tapes (Agilent) and stored at -200C until sequencing.Using multiplexed immunofluorescence in an independent cohort of treatment-naïve pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features that strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

Study phs003865

NCORP: Vitamin D and Breast Cancer Biomarkers (CALGB-70806)

Study ID: CALGB-70806NCT Number: NCT01224678 Alliance for Clinical Trials in OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCORP: Vitamin D and Breast Cancer Biomarkers (CALGB-70806)Trial Description: RATIONALE: Vitamin D may help prevent breast cancer.PURPOSE: This randomized clinical trial is studying vitamin D and breast cancer biomarkers in female patients. Clinical data presented in the following publication(s):PMID 33849913 Disease type(s): Breast Neoplasm - Breast Neoplasm, MiscellaneousNon-neoplastic Disorder - Non-neoplastic Disorder, MiscellaneousClinical Dataset(s) included:NCT01224678-D1 (PMID 33849913): Dataset NCT01224678-D1 is one of 2 datasets associated with PubMed ID 33849913. This dataset contains baseline and change in breast density, baseline characteristics, change in Vitamin D levels, and off treatment reasons.NCT01224678-D2 (PMID 33849913): Dataset NCT01224678-D2 is one of 2 datasets associated with PubMed ID 33849913. This dataset contains data presented in the safety analyses.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

Study phs004250

Disentangling the Effect of Black/African Ancestry from Confounding Variables on Colorectal Cancer Biology

This study examined the effect of African ancestry on AI assisted computation of tumor infiltrating lymphocytes (TIL%) scores from hematoxylin and eosin stained whole slide images (WSI) assembled from three cohorts: 1.) African vs. European ancestry WSI downloaded from the TCGA-COAD-READ database; 2.) African vs. European ancestry WSI assembled from three US medical centers; 3.) Nigerian WSI assembled from a single Nigerian medical center. There were 33 African ancestry WSI suitable for analysis in the TCGA cohort and 48 African ancestry WSI in the independent US cohort. In addition to self-described African ancestry, the additional independent covariables were: 1.) Mismatch repair enzyme-deficient/ microsatellite instability-high vs. MMR-proficient/MSI-Low +microsatellite stable (MMR-d/MSI-H vs. MMR-p/MSI-L+MSS); 2.) Categorical age at diagnosis/resection (75 y); 3.) Sex (Male vs. Female); tumor location (Right vs. Left + Rectum); tumor stage (I+II vs. III+IV), tumor grade [G1+ G1/G2+G2 vs. G2/G3 +G3+mucinous (regardless of G)]. For the 242 TCGA cohort there were 241 parallel whole transcriptome data generated from parallel frozen tumor samples. For the independent US cohort there were 87 parallel targeted whole exome transcriptome data generated from the same formalin fixed paraffin embedded (FFPE) block. The TCGA and independent US cohort computed TIL% scores were correlated separately with CIBERSORTx derived total lymphocyte and T-cell abundance scores, and with CXCL10 and CCL5 gene expression values. mRNA gene expression count data (from STAR processing of the RNA-sequence data) and WSI for the subjects used in this study are available from the Genome Data Commons (GDC).

Study phs004622

Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer: DNA and RNA Sequencing

This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. All participants in this study were female. RNA sequencing (RNA-Seq) data from the same patients were previously published under phs001863. This comprehensive dataset (phs003801) includes all data published under phs001863 and new RNA and DNA data for patients in CALGB 40603.

Study phs003801

Germline Sequence Variation in Cancer Genes Among Rwandan Breast and Prostate Cancer Cases

Inherited genetic information can reduce cancer risk and mortality using protocols for patient ascertainment, testing, counseling, prevention, and treatment. For example, carriers of germline BRCA1/BRCA2 or Lynch Syndrome mutations are at increased risk of breast, ovarian, prostate, endometrial, colorectal, and other cancers. Genetic testing is of clinical value because many mutations are actionable in reducing risk or determining appropriate treatment regimens. There is growing evidence that inherited genetic mutations represent a large proportion of cancer cases in sub-Saharan Africa (SSA). It is also well known that most cancer genetic testing data does not represent the racial and ethnic diversity of the US or global population. Despite the high proportion of cancer cases diagnosed at an early age and late stage, as well as the potential for interventions to reduce cancer risk and death by using genetic tools, genetic testing, counseling, and clinical management protocols have largely not been widely developed in SSA. In order to develop and evaluate the potential for genetic testing in SSA, we propose to undertake a proof of concept feasibility study of hereditary cancer that will contribute data on the prevalence of hereditary cancer mutations in SSA and inform the development of SSA-specific guidelines for cancer genetic testing. In this study, we undertook a pilot evaluation of research genetic testing and counseling in breast and prostate cancer cases in Rwanda that involved genetic testing of breast and prostate cancer cases.

Study phs003927

DNA Repair Capacity for Lung Disease Risk Assessment

A focus of this work was to address the extent to which susceptibility for lung cancer varies by gene-environment-phenotype interactions involving DNA repair capacity and differences in risk from environmental stressors. GWAS from a subset of subjects from the Lovelace Smokers Cohort and New Mexico Lung Cancer cohort were used to derive polygenic risk scores for DNA repair pathways (nucleotide excision, base excision, single strand break, non-homologous, homologous recombination). Logistic regression analysis was used to examine the association between polygenic risk score and lung cancer status. Polygenic risk scores were grouped by quartiles. Only diminished base excision repair was associated with increased risk for lung cancer at the 25-50% quartile and approached significance at the 50-75% quartile.

Study phs004063

National Cancer Institute Multi-Ancestry Genome-Wide Association Study of Kidney Cancer (NCI-3)

The National Cancer Institute (NCI) multi-ancestral genome-wide association study (GWAS) of kidney cancer ("NCI-3") was performed by NCI to further investigate common genetic variants associated with risk of kidney cancer and its two major subtypes across individuals of different ancestries (European, African, East Asian, Latin American). The NCI-3 GWAS includes 12,315 cases and 73,091 controls from 25 centers in North America, South America and Europe, genotyped using the Illumina Global Screening Array v2.0. SNP-level results from this GWAS were combined by meta-analysis with results from two earlier NCI European-ancestry GWAS (RCC; phs000351: 1,311 cases and 3,424 controls and phs001736: 2,417 cases and 4,391 controls), a NCI GWAS of African Americans (phs000863; 255 cases and 375 controls), GWAS conducted at other institutions [International Agency for Research on Cancer (scan 1: 2,438 cases and 5,071 controls; scan 2: 2,781 cases and 2,940 controls), The University of Texas MD Anderson Cancer Center (scan 1: 893 cases and 556 controls, scan 2: 1,241 cases and 1,712 controls) and the Institute for Cancer Research, UK (944 cases and 4,024 controls)] and GWAS analyses of data from three large biobanks (Biobank Japan: 523 cases and 86,306 controls; FinnGen: 2,095 cases and 304,956 controls; UK Biobank: 1,807 cases and 348,824 controls). Only individual-level data from NCI-3 and the two MD Anderson Cancer Center scans are included in this dbGaP submission. All study-specific and meta-analysis summary statistics are included.

Study phs003505

Rearrangements of Viral and Human Genomes at Human Papillomavirus Integration Events and Their Allele-Specific Impacts on Cancer Genome Regulation

We discovered genomic and epigenomic dysregulation originating at sites of human papillomavirus (HPV) integration following the Oxford Nanopore long-read analysis of 72 cervical cancer genomes. The integration events had allele-specific effects on the genome, methylome, and transcriptome, which sometimes resulted in the activation of cancer genes. We also examined the 72 samples using Illumina short-read analysis in phs000528. We also produced long-read cDNA-sequencing data on 29 cervical cancer samples from phs000528 (of which 27 also have long-read WGS data available) for further analysis of HPV-human transcripts derived from HPV integration events.

Study phs003780

HINTS Geo-Coded Data 2019 (HINTS 5 Cycle 3)

The Health Information National Trends Survey (HINTS) is a nationally representative survey which has been administered every few years by the National Cancer Institute since 2003. HINTS 5 includes four mail-mode data collection cycles over the course of four years. The third round of data collection for HINTS 5 (Cycle 3) was conducted from January 22 to April 30, 2019 with a goal of obtaining 3,500 completed questionnaires. A push-to-web pilot test was conducted alongside the fielding of Cycle 3 (referred to as the Web Pilot). The Web Pilot was conducted from January 29 to May 7, 2019 with a goal of obtaining 2,046 additional completed questionnaires. A total of 5,438 respondents are included in the final sample.

Study phs004216

Incidental Detection of Maternal Neoplasia through Non-Invasive Cell-Free DNA Analysis (IDENTIFY), a Natural History Study

Prenatal cell-free (cf) DNA sequencing for fetal aneuploidy incidentally detects circulating tumor DNA in the plasma of asymptomatic pregnant women. Distinguishing the subset of women with malignant tumors detected by prenatal sequencing from those with benign conditions, such as uterine fibroids, is critical to maternal medical management. The Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Sequencing (IDENTIFY) study at the National Institutes of Health in Bethesda, MD, offers standardized cancer screening and cfDNA sequencing to asymptomatic or minimally symptomatic pregnant women with nonreportable prenatal cfDNA sequencing results. We previously reported that whole-body magnetic resonance imaging (WB-MRI) and a specific genome-wide sequencing pattern of chromosomal gains and losses involving three or more chromosomes could reliably differentiate which women had cancer. We continue to explore additional noninvasive biomarkers to identify the subset of women with nonreportable prenatal cfDNA sequencing results who have cancer and to predict tissues of origin, particularly when patients or their providers are reluctant to pursue diagnostic testing, WB-MRI studies are unavailable, or imaging findings are indeterminate. Here, cfDNA sequence analysis was performed to identify cancer driver somatic mutations that might aid in distinguishing between pregnant women who have a high likelihood of occult malignancy from those who do not. In this pilot study, prospectively collected blood samples from 65 pregnant or postpartum women with and without occult cancers were analyzed blindly for cfDNA somatic mutations in 275 cancer-associated genes.

Study phs004107

GU16-257: Neoadjuvant Gemcitabine, Cisplatin, Plus Nivolumab in Patients with Muscle-Invasive Bladder Cancer with Selective Bladder Sparing

This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to define the role of clinical complete response (cCR) in predicting benefit in patients opting to avoid cystectomy. Primary Objectives Determine the cCR rate with gemcitabine, cisplatin, plus nivolumab;Determine the ability of cCR (cT0 or cTa) to predict benefit from treatment. Benefit was defined as, among the patients achieving a cCR, either being (a) 2-year metastasis-free in patients forgoing immediate cystectomy or (b) FindingsSeventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of the 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1).

Study phs003372

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