Search Results - EGA European Genome-Phenome Archive

Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

This dataset contains all available targeted exon sequencing bam files from our study, "Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer". Patient identifiers are denoted by the first segment of the sample aliases (e.g. "P1"), and additional information is appended to reflect which serial sample is referenced (1st, 2nd, 3rd, etc.), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("WBC"). All samples were sequenced using Illumina technology.

Dataset EGAD00001006122

Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients

Background: Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods: Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~6x coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results: We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and SCNAs. We further combined global and regional fragmentation pattern into a machine learning classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion: In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring.

Study EGAS00001006490

The dataset for Detection and characterization of lung cancer using cell-free DNA fragmentomes

The dataset for Detection and characterization of lung cancer using cell-free DNA fragmentomes includes 872 bam files from whole genome next-generation sequencing on the Illumina HiSeq2500. The samples analyzed include plasma samples from healthy individuals and patients with cancer.

Dataset EGAD00001007796

STAMPEED: Northern Finland Birth Cohort 1966 (NFBC1966)

The Northern Finland Birth Cohorts program (NFBC) was initiated in the 1960s in the two northernmost provinces of Finland to study risk factors involved in pre-term birth and intrauterine growth retardation, and the consequences of these early adverse events on subsequent morbidity and mortality. The uniqueness of NBFCs is that the data of the cohorts were obtained from early fetal life (including maternal health during pregnancy) to adulthood. The NFBC1966 includes 12,058 live births to mothers in the two northern-most provinces of Finland. Two decades later, a second cohort of 9432 births was obtained (NFBC1986). In NFBC1966 pregnancies were followed prospectively from the first antenatal contact (10-16th week). After birth, the offspring were examined and then again underwent clinical evaluation at ages 1y, 7y, 14-16y and 31y. At each visit, a wide range of phenotypic, lifestyle and demographic data were gathered by questionnaires and clinical examinations. For the most part, NFBC1986 has undergone similar evaluations to NFBC1966. Linkage to national registries includes hospitalization, deaths, education, medication, pensions, and provides up-to-date demographic and clinical information for members of both cohorts. DNA samples were obtained from 5,923 subjects from NFBC1966 and 6688 subjects from NFBC1986. Data coverage, 96% of all births in 1966 and 99% in 1986, is highly representative for the whole population. The NFBC program comprises more than 20 different projects coordinated by the Center of Lifecourse Disease studies in Northern Finland (COLD) at Oulu University. The prospective data collected from the NFBCs form a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioral risk factors. The genome-wide association (GWA) study sponsored through the STAMPEED program of NHLBI employed genomic DNA samples previously collected by the NFBC1966 study and stored in the DNA repository of the National Institute for Health and Welfare, Finland. This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to metabolic and cardiovascular diseases (CVD). In addition to de-identified genome wide genotypic data, a selected list of phenotypic data related to CVD including weight, height, BMI, HDL, LDL, total cholesterol, triglyceride, glucose, insulin and fasting status, are also available in dbGaP. A summary of the GWAS for the NFBC1966 cardiovascular risk traits can be found in Sabatti et al., Nature Genetics 41: 35-46, 2009, PMID: 19060910. The version 2 release of this study contains sequence data from seventeen loci associated with levels of triglyceride, HDL-C, LDL-C, total cholesterol, fasting plasma glucose, and fasting plasma insulin (Kathiresan et al. 2008, Willer et al. 2008, Sabatti et al. 2009, Dupuis et al. 2010, Teslovich et al. 2010). At each locus, protein-coding regions and 5' and 3' untranslated regions of genes nearest to single nucleotide polymorphisms showing genome-wide significant association with metabolic syndrome-related traits, were sequenced. Targeted Illumina sequencing of 78 genes (~270kb) using 150bp probes was performed on 4943 subjects of the Northern Finland Birth Cohort 1966 (NFBC1966). Whole exome sequencing on the Illumina platform was carried out on 586 of those participants. The sequencing study is part of a larger project that is funded by the National Human Genome Research Institute's Allelic Spectrum in Common Disease Initiative, and comprises sequence data from more than 7000 individuals in two Finnish cohorts: NFBC1966 and the Finland-United States Investigation of NIDDM Genetics (FUSION) study.

Study phs000276

TruSight Oncology 500 ctDNA targeted sequencing data from endometrial cancer patients

This dataset contains targeted sequencing data generated using the TruSight Oncology 500 ctDNA v2 assay from plasma-derived cell-free DNA of dMMR endometrial cancer patients, at baseline and C3D1 of immunotherapy. Sequencing was performed on Illumina NovaSeq600. Dataset includes aligned sequencing files in BAM format generated using the DRAGEN TruSight Oncology 500 ctDNA v2.6.0 analysis pipeline.

Dataset EGAD50000002262

Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

We set out to determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. We collected and sequenced 77 plasma cell-free DNA samples from 53 newly diagnosed patients with mCSPC. Targeted sequencing was also performed on DNA from 48 diagnostic prostate tissue samples.

Dataset EGAD00001004526

lymphoma plasma cfRNA

Dataset contains total RNA sequencing data from plasma of 65 different human donors: 30 diffuse large B-cell lymphoma (DLBCL) and 13 primary mediastinal large B-cell lymphoma (PMBCL) patients, and 22 cancer-free controls. Samples were sequenced on a NovaSeq 6000 and are provided in FASTQ format.

Dataset EGAD00001010259

Ancestry and somatic profile predict acral melanoma origin and prognosis – RNA

Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

Dataset EGAD00001015756

Nanopore sequencing from liquid biopsy: analysis of copy number variations from cell-free DNA of lung cancer patients

Study EGAS00001004975

Clinical and demographics data from IMvigor210, IMvigor211, IMvigor130 and IMvigor010

Clinical data include demographics (gender, race), specimen type (primary vs. metastatic), tract (upper vs. lower), liver metastasis status, PD-L1 IHC, tumor mutation burden, CD8 T cell infiltration status, neutrophil enrichment score, treatment arm, objective response rate, overall survival and progression free survival, and ctDNA status (IMvigor010 only) for 2803 patients across the four IMvigor trials.

Dataset EGAD50000001101

Durable clinical impacts and mechanisms of action and resistance in histone K27 methylation-targeting epigenetic therapy

Epigenomes allow the rectification of disordered cancer gene expressions, thereby providing new targets for pharmacological interventions in cancer therapy. The clinical utility of targeting histone H3 lysine tri-methylation (H3K27me3) as an epigenetic hallmark has been demonstrated. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumor cells remain unclear. Here we show the potency and mechanisms of action and resistance of a newly developed EZH1/2 dual inhibitor, valemetostat, in the clinical trials of patients with adult T-cell leukemia/lymphoma (ATL). Valemetostat administration reduced the tumor size and demonstrated durable clinical benefits. Integrative single-cell analyses of patients before and after the administration of valemetostat showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, such as tumor suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. The acquired mutations at the EZH2???compound interface result in the propagation of the clones with re-increased H3K27me3. In patients free of this mutation, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation at the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting chromatin homeostasis might provide opportunities for further sustained epigenetic cancer therapies.

Study JGAS000553

Stratified Medicine Paediatrics (SMPaeds): molecular profiling of relapsed paediatric cancer

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tumour DNA and cfDNA were analysed by targeted panel sequencing and low coverage whole genome sequencing.

Study EGAS50000000549

A somatic reference standard for cancer genome sequencing.

Paired PCR-free whole genome sequencing data of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. The data was generated with mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions.

Dataset EGAD00001002142

Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

Adapted from manuscript in review: Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC) but there have been few whole genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. These include highly recurrent tandem duplications involving an upstream enhancer of AR. A subset of cases also displayed a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC nominate new alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the noncoding mCRPC genome remain to be discovered.

Study phs001577

Circulating RNA profiles of healthy and preeclamptic pregnancies

This prospective study investigated whether circulating RNA (C-RNA; cell free RNA present in the bloodstream) measurements could non-invasively monitor pregnancy status, with emphasis on detecting molecular markers associated with preterm preeclampsia. Whole blood samples were collected from pregnant women at the time of diagnosis with early-onset preeclampsia with severe features. Blood samples were also obtained normotypical control pregnancies and from patients diagnosed with late-onset preeclampsia for comparison. For all samples, C-RNA was extracted from 4 mL blood and whole transcriptome enrichment performed on cDNA libraries prior to sequencing to a target depth of 50M reads on an Illumina HiSeq 2000 platform. Throughout the course of this work, whole transcriptome RNA sequencing data was obtained from 289 C-RNA samples collected from 178 subjects. The complete dataset consists of samples from the following cohorts: Illumina Preeclampsia Cohort (iPEC): 40 pregnancies at the time of early-onset preeclampsia diagnosis and 73 gestational age-matched controls PEARL preeclampsia cohort: 12 early-onset and 12 late-onset preeclampsia patients PEARL healthy control cohort: 152 longitundinal samples collected from 41 healthy pregnancies

Study phs002017

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients with Advanced Lung Adenocarcinoma

We retrospectively collected patients (n=1047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r=0.403, P<0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT >6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤6.9 months set. This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Study EGAS00001004546

Fragmentomics analyses of urinary cfDNA for urologic cancers

This dataset contains sequencing data of human urinary cell-free DNA. Whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) was performed after DNA extraction from the urine samples. All samples were pair-end sequencing on Illumina system and were aligned to human genome GRCh37 (hg19). WGS and WGBS reads were aligned by SOAP2 and Methyl-Pipe, respectively. The dataset includes samples from healthy subjects, haematuria (non-cancer), and patients of bladder, kidney, or prostate cancer. Pair-end FASTQ files were provided for all the samples mentioned above.

Dataset EGAD50000002068

Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

Study EGAS00001002511

Study of Melanoma Risk in Australia and the United Kingdom

The results from a small number of melanoma GWAS have been published. Initial studies identified several pigmentation- and nevus-associated loci that mediate an effect on melanoma risk, however, these studies were somewhat limited in that sample number (hence power) was low, they used first-generation low density SNP arrays, or used pools of DNA samples. Subsequently, additional melanoma GWAS have been completed, including a "Phase 2" study by the International Melanoma Genetics Consortium (GenoMEL), a full GWAS of the Australian sample resource previously used in a pooled-DNA GWAS, and study conducted through the MD Anderson Cancer Center and the Brigham and Women's Hospital. The groups who performed these studies have recently shared data and replicated a number of new melanoma susceptibility loci. Aside from the identification of novel loci, there are two additional notable outcomes of these studies. Firstly, an examination of the observed versus expected test statistics (Q-Q plot) from the Australian study, even after removing data from SNPs within known replicated susceptibility loci, reveals that there remains an excess of positive results. Similarly, the latest GenoMEL study finds almost three times as many SNPs reaching p-values between 10-4 and 10-5 as would be expected by chance. In the light of other studies of complex traits [1], these data suggest that studies based on additional melanoma samples from the same population are likely to identify an even larger "polygenic tail" and should prove invaluable in identifying and characterizing the underlying loci. A second observation, is that the effect size for replicated associations differs very little between GWAS. Given the strong effect of ultraviolet radiation (UVR) on risk of melanoma this might be expected to affect penetrance, particularly in the Australian and English samples, which are ethnically similar, but have very different sun exposures. We hypothesize that those SNPs whose effects are strongly mediated by UVR exposure may have smaller marginal effects on risk and are therefore harder to detect initially, suggesting a whole category of genetic effects that are unexplored.Indeed, most melanoma GWAS performed to date used samples from both European and Australian populations in discovery and or replication, and thus, existing studies have been poorly powered to detect associations with a wide difference in effect between these low- and high-UVR populations. Here, we wish to pursue this hypothesis further and plan to genotype additional cases drawn from the English and Australian populations. This will serve two complementary objectives: firstly, it will greatly increase our collective power to detect additional new melanoma risk alleles; secondly, it will highlight associations that are stronger specifically within the context of either low-UVR or high-UVR exposure environments. We posit that these data will be invaluable, not just for identifying novel melanoma-associated loci, but also for addressing gene-environment interactions. We have available a collection of valuable resources to help fulfill our aims. These include a considerable number of well-characterized and ungenotyped Australian and UK melanoma cases, as well as existing genotype data from sets of Australian and UK cases and population-based controls. We propose the following Specific Aims: To extend our current collective melanoma GWAS by genotyping a large number of additional UK and Australian cases. To jointly analyze these data and identify new melanoma risk loci. To determine whether pre-existing and new melanoma risk alleles show different degrees of association between the English and Australian populations, and assess whether these differences might be due to differences in sunlight exposure.

Study phs000519

National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository Human Variation Panels including 100 African-Americans (HD100AA), 100 Caucasians (HD100CAU), 100 Han People of Los Angeles (HD100CHI) and 100 Mexican American Community of Los Angeles (HD100MEX)

The Human Genetic Cell Repository is sponsored by the National Institute of General Medical Sciences (NIGMS) with the mission of supplying scientists with the materials for accelerating disease gene discovery and functional studies. The resources available include highly-characterized, contaminant-free cell cultures and high quality, well-characterized DNA samples derived from these cultures, both subjected to rigorous quality control. The Repository was established in 1972 at Coriell and contains more than 9,500 cell lines, primarily fibroblasts and transformed lymphoblasts. The Repository has a major emphasis on inherited diseases and chromosomally aberrant cell lines. In addition, it contains a large collection dedicated to understanding human variation that includes samples from populations around the world, the CEPH collection, the Polymorphism Discovery Resource, Human Variation and many apparently healthy controls. The Human Variation collection provides cell lines and DNA samples from a variety of populations. The panels of African-Americans (HD100AA) and Caucasians (100CAU) used for this study are comprised of samples present in the Repository that were originally collected over the years from apparently healthy people to be used as "controls", for example, unaffected family members of persons with identified mono-genetic diseases. The samples for the Han people of Los Angeles (HD100CHI) and the Mexican American Community of Los Angeles (HD100MEX), however, were collected relatively recently from volunteers, identified as member of these communities, specifically for use in these panels. The Coriell Genotyping and Microarray Center in conjunction with the NIGMS repository used the Affymetrix Genome-Wide Human SNP 6.0 platform to genotype 400 samples from the NIGMS human variation panels. The populations genotyped included Americans of African, Caucasian, Mexican, and Han Chinese ancestry. The Affymetrix SNP 6.0 array detects approximately 940,000 SNPs and provides copy number information for more than 900,000 additional locations across the genome.

Study phs000211

Immunohistochemical and molecular pathological search in gastrointestinal tumors

Purpose: RSPO fusions are recently identified recurrent genetic alterations in colorectal cancer (CRC), which lead to WNT pathway activation and are potential therapeutic targets. We aimed to investigate the clinicopathological and molecular features of RSPO fusion-positive CRCs. Experimental Design: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription polymerase chain reaction. RSPO fusion-positive tumors were characterized for their clinicopathological features and subjected to whole exome sequencing (WES). Results: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of 5 with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 females and 12 males with the median age of 64 years. Thirteen tumors were located in the right colon, 8 were in the left colon, and 8 were in the rectum. Histologically, most of the tumors (24/29, 83%) were classified as adenocarcinomas, not otherwise specified. However, about half of the tumors (13/29, 45%) had a focal or extensive mucinous component, which is significantly more frequent compared with RSPO fusion-negative tumors (13%; p = 8.1 �� 10-7). Four tumors (14%) were mismatch repair-deficient, three of which were associated with MLH1 promoter methylation. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 cases (93%). In contrast, pathogenic mutations in major WNT pathway genes other than RSPO fusions were virtually absent. The presence of an RSPO fusion tended to show shorter overall and recurrence-free survivals in stage II and III patients although the differences were not significant. Conclusions: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features. The mutual exclusivity with other WNT pathway gene alterations supports RSPO fusions as valid therapeutic targets in CRC.

Study JGAS000538

Cell Type-Specific and Disease-Associated eQTL in the Human Lung

This study was conducted to investigate the genetic control of gene expression in a cell-type and context-specific manner in the human lung. We performed single-cell RNA-sequencing (scRNA-seq) of lung tissue from 66 Interstitial Lung Disease (ILD) cases and 48 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types. The scRNA-seq data presented here include previously published (PMID 34262047) and unpublished samples. ILD tissue samples were obtained from lungs removed at the time of lung transplantation at either Vanderbilt University Medical Center (VUMC) or the Norton Thoracic Institute (NTI). Control tissue samples were obtained from lungs declined for organ donation either at the Donor Network of Arizona (DNA) or VUMC. The self-reported ethnicities of donors were 66.7% European, 9.6% African American, 17.5% not available (N/A), and 6.1% other. The smoking history includes 46.5% ever smoker, 29.8% never smoker, 23.7% N/A. For genotyping, flash-frozen tissue in DNA/RNA shield was homogenized via a bullet blender. Genomic DNA was extracted using Zymo Quick DNA/RNA microprep plus kit. Library preparation and low-pass Whole Genome Sequencing (WGS) were carried out at TGen or by Gencove Inc. At TGen, libraries were prepared using PCR-free Watchmaker kits (Watchmaker Genomics) with 200 ng input. Genomes were sequenced on NovaSeq at low coverage (typically 0.4–1x). The resulting sequence data were processed and imputed using Gencove's imputation platform.

Study phs003521

Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

Study phs003483

Systolic Blood Pressure Intervention Trial (SPRINT-Imaging)

Available DataSystolic Blood Pressure Intervention Trial, SPRINT-Imaging, provides access to ECG signals data from the SPRINT clinical trial. The clinical phenotyping and outcomes data from the trial are associated with SPRINT-BioLINCC, phs003483.ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease. BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group. DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy. Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

Study phs003566

RNA sequencing of periprostatic fat after a 6 month deep androgen deprivation therapy

Androgen deprivation therapy treated patients (n=11) were recruited from an open label neoadjuvant phase II study in which patients with high-risk disease received a ‘supercastration’ regimen consisting of degarelix 240/80 mg subcutaneously every four weeks; abiraterone acetate 500 mg orally daily titrating upwards every two weeks by 250 mg to a final dose of 1000 mg daily; bicalutamide 50 mg orally daily; and prednisolone 5 mg orally twice daily for a total of 6 months (Australian New Zealand Clinical Trials Registry 12612000772842). Untreated patients with similar pre-treatment characteristics were obtained from a prospective prostatectomy biorepository22,23. Prior to ligation of the dorsal venous complex and prostate pedicles, the anterior prostate was defatted and the specimen was removed immediately, placed in a sterile container and transferred on ice for long-term storage in the vapour phase of liquid nitrogen. A total of 50–100 µg of adipose tissue was separated from fresh frozen samples stored at −160°C. RNA was isolated using the Qiagen RNeasy Lipid Tissue Mini Kit and eluted in 35 µL nuclease-free water. 0.5–1 µg of total RNA was used as the input for cDNA library synthesis using TruSeq RNA Sample Prep Kit v2 (Illumina), and libraries were constructed according to manufacturer’s instructions. Samples were sequenced on a HiSeq 2500 (Illumina) using 101 base paired-end chemistry, aiming for 50 million mapped paired-end reads per sample.

Dataset EGAD00001004971

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