Search Results - EGA European Genome-Phenome Archive

Atherosclerosis Risk in Communities Study (ARIC-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. At present, the ARIC sIRB has determined that ARIC data cannot be shared with for-profit entities.Related Studies Other ARIC data available include: Imaging studies (ARIC-Imaging), Genetics and genomics (ARIC, phs000280.v8.p2), Collaborative Cohort of Cohorts for COVID-19 Research (C4R): ARIC (phs002988.v1.p1), and as a component of the Sleep Heart Health Study (SHHS-BioLINCC, phs003637.v1.p1). Available Data Data available for request include ARIC v1-v8 examination cycles, collated annual follow-up communication data for contact years 2-32, and follow-up for mortality, heart disease, and stroke events through 2019. Also included are data from ancillary studies. Objectives The objectives of ARIC are to: 1) investigate associations of factors, including those not previously measured in cohort studies, with prevalence of atherosclerosis and incidence of CHD, clinical stroke and other cardiovascular diseases; and 2) measure cardiovascular disease occurrence and trends and relate these to community levels of, and changes in, risk factors, medical care and atherosclerosis. Background At the time of project initiation, the NHLBI had long recognized the need for longitudinal studies to identify the biochemical and physiological markers and specific environmental factors which place individuals at high risk for the major atherosclerosis diseases. The development of reliable ultrasound examination of peripheral arteries enhanced the expected benefit of such studies. Community surveillance planning began for ARIC in response to recommendations of the 1978 NHLBI Workshop on the Decline in CHD Mortality and has been extended in its purpose to evaluate the large geographic differences in U.S. mortality. Participants Black and white men and women, age 45-64 at entry; sample size: 15,792. Design ARIC is a large-scale, long-term prospective study that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women from four geographically diverse communities. The project has two components: community surveillance of morbidity and mortality; and repeated examinations of a representative cohort of men and women in each community. The community surveillance involves abstracting hospital records and death certificates and investigating out-of-hospital deaths. The representative cohorts include approximately 4,000 persons from each community. Community surveillance data includes detailed hospital record abstraction, ECG tracings, and event adjudication. Data from out-of-hospital events in the community include physician, informant, and coroner questionnaires as well as death certificate data and event adjudication. Community surveillance ended in 2014.Cohort participants were examined four times at three year intervals between 1987 and 1998, and have been continuously contacted annually to update their medical histories. Atherosclerosis was measured by carotid ultrasonography. Risk factors studied include: blood lipids, lipoprotein cholesterols, and apolipoproteins; plasma hemostatic factors; blood chemistries and hematology; sitting, supine and standing blood pressures; anthropometry; fasting blood glucose and insulin levels; ECG findings; cigarette and alcohol use; physical activity levels; dietary aspects; and family history. Clinic visits were restarted in 2011 with ARIC visit 5.

Study phs003738

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data uncovers a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

Study EGAS00001004763

Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients.

Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients. The sequencing was performed by Illumina HiSeq 4000. Background and aims: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) could reflect nearly the entire mutation spectrum in given tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC).Methods: Thirty-two multi-regional HCC samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS). ITH extent was measured by the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Matched cfDNAs were also analyzed by WES and TDS. Profiling efficiencies of single tumor specimen and cfDNA were compared and the one better depicted mutational landscape was selected to screen therapeutic targets.Results: We found variable extents of ITH in HCCs and observed branched and parallel evolution patterns. ITH level decreased at higher sequencing depth of TDS than that measured by WES (28.1% vs 34.9%, P < 0.01) but it remained unchanged upon additional samples analyzed. TDS of single tumor specimen detected an average of 70% the total mutations in HCC. Although more mutations were detected in cfDNA under TDS than WES, an average of 47.2% total HCC mutations uncovered by cfDNA suggested tissue outperform cfDNA and the latter may serve as alternative in profiling HCC genome. Consequently, TDS of single tumor tissue in 66 patients and cfDNAs in four unresectable HCCs identified 38.6% (26/66 and 1/4) patients bearing therapeutic targets.Conclusions: TDS of single tumor specimen could largely circumvent ITH to uncover mutations indicative of target therapy in HCC.

Dataset EGAD00001003278

Development and Use of Network Infrastructure for High-Throughput GWA Studies

The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer's Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt's BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer's disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer's Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer's disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has ≥ 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70°C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under §46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt's broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

Study phs000234

Biological Determinants of Peritoneal Dialysis Outcomes

Peritoneal Dialysis (PD) is a technique for treating kidney failure where fluid is instilled into the body's peritoneal cavity. Fluid and solutes travel across the peritoneum, and this is critical to successful PD. Studies have shown that certain demographic and clinical variables explain a small part of the variability in baseline peritoneal solute transfer rate and water transfer function across the peritoneum. This study sought to identify the common genetic variants associated with the baseline peritoneal function in patients starting treatment with PD and change in function upon treatment with PD. This study has two specific aims: Aim 1: To identify and validate genetic loci that influence the peritoneal solute transfer rate (PSTR) at start of PD. Aim 2: To identify and validate genetic loci in pre-specified biologic pathways with change in peritoneal ultrafiltration capacity. This study incorporates data from participants' peritoneal solute transfer rate in their first ever peritoneal equilibrium test (PET) and changes in the transfer of water across the peritoneal membrane over time in a sub-group of participants, demographic information, and results from laboratory analysis of DNA, blood, and dialysate. This study comprises patient populations from pre-existing biorepositories in Europe, and prospectively enrolled participants in United States, Canada, United Kingdom, and Australia. Clinical data related to the participants' peritoneal solute transfer rate from their first ever Peritoneal Equilibrium Test (PET), demographic information, and change in ultrafiltration capacity over time, are correlated with various genetic markers of interest. For individuals enrolled prospectively, blood and dialysate were collected at the first study visit. Annually, subjects either underwent a PET as standard of care or perform an additional 4-hour dwell as part of the study. These subsequent measures were utilized to determine change in ultrafiltration capacity over time. Inclusion criteria included adults over the age of 20 who are able to provide consent and had a record of a PET within 6 months of starting PD. Subjects with missing outcome data and that did not pass genotyping QC were excluded. Genotyping was performed in two batches using the Illumina InfiniumOmni2-5-8v1-3_A1 array with 2,372,784 single nucleotide variants (SNVs) in the first batch (n=1957). The second genotyping batch (n=1053) was on the InfiniumOmni2-5-8v1-4_A1 array with 2,382,209 SNVs. Imputation was performed using the Michigan Imputation Server and the HRC1.1 genotype reference. The Institutional Review Board of the University of Washington has “dbGaP-certified” the consent forms used to enroll participants in Australia, Canada, and United States and the genotype-phenotype data from the participants (n=827) deposited in the public repository. Furthermore, it has been determined that under the EU-GDPR regulations, depositing data of participants enrolled in UK, Belgium, and Sweden (n=2,023) into dbGaP “serves no lawful purpose” as the consent form used for enrolling participants did not obtain explicit permission for depositing data in a public repository.

Study phs002996

Jackson Heart Study (JHS-BioLINCC)

Accessing Data: Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Related Studies: Other Jackson Heart Study data available include: Imaging studies (JHS-Imaging), Genetics and genomics (The Jackson Heart Study, phs000286.v7.p2), and Collaborative Cohort of Cohorts for COVID-19 Research (C4R-JHS, phs002907.v1.p1): Jackson Heart Study (phs002907.v1.p1).Available Data: Data available for request include Jackson Heart Study visit 1-3 examination cycles, collated annual follow-up communication data through 2016, and follow-up for mortality, heart disease, and stroke events through 2014.Objectives: The objectives of the Jackson Heart Study are to: 1) investigate the associations of biological, psychosocial, and behavioral factors with the incidence atherosclerotic events and health outcomes in an African American cohort; and 2) increase access to and the participation of African American populations and scientists in biomedical research and professions.Background: It has long been recognized that African Americans share a disproportionate burden of deleterious health outcomes including diabetes, hypertension, kidney disease and early onset of cardiovascular disease. The Jackson Heart Study was initiated in 2000 to explore potential mechanisms and mediators of health outcomes in a large African American cohort. In addition, the JHS conducts a variety of community education and outreach activities to promote healthy lifestyles to reduce disease risk burden and student training programs to promote and support public health research.Participants: African American men and women, age 35-84 at entry. Of the 5306 cohort members enrolled in the study, the data repository contains data from 3,883 that provided informed consent to share their data with investigators not affiliated with the study.Design: Participants were enrolled in the study from 2000-2004 from urban and rural areas of three counties (Hinds, Madison and Rankin) in the Jackson, MS metropolitan statistical area. Participants were enrolled from each of 4 recruitment pools: a random sample component (17%), volunteer component (30%), currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study (31%), and secondary family members (22%). Recruitment was limited to non-institutionalized adult African Americans age 35-84 years, except in the family cohort where those age ≥21 years were eligible. The final cohort of 5,306 participants includes 6.59% of all African American residents aged 35-84 (N=76,426, US Census 2000). Data collection at the baseline exam included a medical history, physical examination, blood/urine analytes and interview questions on areas such as: physical activity; stress, coping and spirituality; racism and discrimination; socioeconomic status; and health care access.The current release of the Jackson Heart Study includes data collected at baseline, exam 2 (2005-2008), and exam 3 (2009-2013). Annual follow-up and surveillance of clinical cardiovascular events is ongoing.

Study phs003740

A Genome-Wide Association Study in Patients Experiencing Breast Events While Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer on NCIC CTG Trial MA.27

Source of patients:The source of the patients for this genome-wide case-control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been estrogen receptor (ER) and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. The final results of this study have been published, see Goss et al., 2013 (23358971). The patients in this analysis came from three cohorts: Cohort 1 consisted of 870 patients genotyped on the Illumina Human610-Quad BeadChip studied in a GWAS with the phenotype of musculoskeletal adverse event, see Ingle et al., 2010 (20876420), Cohort 2 consisted of 882 patients genotyped on the Illumina OmniExpress platform studied in a GWAS with the phenotype of fragility fractures, see Liu et al., 2014 (25148458), and the remaining 2913 patients were genotyped with the Illumina OmniExpressExome platform.

Study phs001043

Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study

Background: Follicular lymphoma (FL) is an indolent, yet incurable B-cell malignancy. A subset of patients experience increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immuno-chemotherapy. The nature of tumor clonal dynamics leading to these clinical endpoints is poorly understood and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the timecourse of FL clinical histories. Methods and Findings: Using a combination of whole genome sequencing, targeted deep sequencing and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in n=15 transformation patients and n=6 progressors, and measured their change in abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimen. This pattern was independent of time to transformation and treatment modality. By contrast, progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immuno-chemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in a validation cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical endpoints. We found 12 genes were more commonly mutated in transformed samples than in preceding FL, including TP53, B2M, CCND3, GNA13, S1PR2 and P2RY8. Moreover, 10 genes were more commonly mutated in diagnostic specimens of early progressors including TP53, BTG1, MKI67 and XBP1. Conclusions: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implication for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Study EGAS00001001709

NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

Study phs000988

Molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (N2M2/NOA-20 phase I/IIa umbrella trial)

Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N2M2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients.

Study EGAS00001008033

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