Search Results - EGA European Genome-Phenome Archive

APOBEC3 mutagenesis drives therapy resistance in breast cancer

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer, however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

Study EGAS50000000875

A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab in Stage IV Squamous Cell Lung Cancer

Lung-MAP (S1400, NCT02785952) was a multicenter, open-label, phase III randomized clinical trial. The Lung-MAP-I substudy (S1400I) was conducted from December 2015 to April 2018, through the National Clinical Trials Network and led by the SWOG Cancer Research Network. The trial compared nivolumab plus ipilimumab (nivo+ipi) with nivolumab monotherapy (nivo) in patients with chemotherapy-pretreated, immunotherapy-naïve, advanced squamous non-small cell lung carcinoma (sqNSCLC). Two hundred fifty-two patients were randomly assigned to receive nivo+ipi (n = 125) or nivo (n = 127). The clinical efficacy endpoints were overall survival, progression free survival, duration of response, and best objective response by RECIST 1.1. Multi-omic translational analysis was performed in collaboration with the the CIMAC–Cancer Immunologic Data Commons (CIDC) Network using available tumor tissue samples and blood samples (n = 160) submitted for Lung-MAP screening and provided by the SWOG tissue bank.

Study phs003412

CIDR: NCI Genome Wide Predictors of Survival in Colorectal Cancer

CIDR/Molecular Correlates: This study genotyped archived blood samples from colorectal cancer cases participating in clinical trials. The goals of this project were to identify genetic variants associated with survival outcomes treatment and treatment-related severe adverse events among patients with colorectal cancer. Another goal was to examine the impact of adding information on germline genetic loci to existing prognostic models. MOSAIC: Multicenter International Study of Oxaliplatin/ 5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). A randomized, open label efficacy trial to evaluate the FOLFOX regimen versus LV5FU2 in the adjuvant treatment of stage II and III colon cancer. The primary end point was disease-free survival. CPT.ES1.604: Randomized phase 3 study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic CRC. The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate). 03-TTD-01: The purpose of this phase III, multicenter, randomized, open-label study is to evaluate the safety and efficacy of combination therapy with capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer. The primary outcome measure is time to disease progression. Secondary outcome measures are to determine safety of combination, objective response rate, time to onset of response, duration of response, time to treatment failure, one year survival time, and overall survival time. 03-TTD-01: The purpose of this phase III, multicenter, randomized, open-label study is to evaluate the safety and efficacy of combination therapy with capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer. The primary outcome measure is time to disease progression. Secondary outcome measures are to determine safety of combination, objective response rate, time to onset of response, duration of response, time to treatment failure, one year survival time, and overall survival time. N0147: Randomized phase III clinical trial for adjuvant therapy in stage III colon cancer patients enrolled at institutions across North America. Originally designed to compare three different chemotherapy regimens, and then later expanded to evaluate adding cetuximab to each original arm (leading to six total arms). Further modification later added pre-screening for KRAS mutation status, with the resulting goal to assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Main outcome of interest is disease-free survival in patients with wild-type KRAS, while secondary end points included overall survival and toxicity. N9741: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients who have advanced, recurrent, or metastatic colorectal cancer that cannot be treated with surgery or radiation therapy. C-08: A Phase III Clinical Trial Comparing Infusional 5-Fluorouracil (5-FU), Leucovorin, and Oxaliplatin (mFOLFOX6) Every Two Weeks With Bevacizumab to the Same Regimen Without Bevacizumab For the Treatment of Patients With Resected Stages II and III Carcinoma of the Colon. The primary aim of the trial was to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging disease-free survival and the secondary aim was to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging survival.

Study phs001290

Whole exome sequencing of cell-free DNA reveals temporo-spatial heterogeneity and identifies treatment-resistant clones in neuroblastoma

Background: Neuroblastoma (NB) displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Patients and Methods: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 NB patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of Single Nucleotide Variants (SNVs) and Copy Number Alterations (CNAs), with 41% and 93% of all detected alterations common to the primary NB and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate timepoints during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2. Conclusion: Modelisation of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating towards tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies.cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target.

Study EGAS00001002705

Exome sequencing data for the DIRECT study.

This dataset contains all available fastq files for gemline, baseline plasma/biopsy, and response assessment patient samples for the DIRECT study. The total number of samples was 729 (188 germline, 190 baseline plasma, 159 baseline biopsy, and 192 response assessment). The dataset files were generated from targeted (exome) Illumina sequencing performed on paired biopsy tissue and plasma cell free DNA.

Dataset EGAD50000001409

non-malignant plasma cfRNA

Dataset contains mRNA capture sequencing data from plasma of 125 different human donors: 88 patients with a non-malignant disease and 37 cancer-free controls. Samples were sequenced on a NovaSeq X and sequencing data is provided in FASTQ format.

Dataset EGAD50000001806

Noncoding Mutational Analysis of DLBCL Genomes

146 DNA samples obtained from 73 DLBCL patients (matching tumor and normal) were sequenced with PCR free 1.0 genome shotgun sequencing. All files are in bam format.

Dataset EGAD00001004142

Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

Non-invasive prenatal testing (NIPT) is a powerful screening method for fetal aneuploidy detection, relying on laboratory and computational analysis of cell-free DNA. Although several published computational NIPT analysis tools are available, no comprehensive and direct accuracy evaluations of these tools is published. Here, we evaluate and determine the precision of five commonly used computational NIPT aneuploidy analysis tools, considering diverse sequencing depth (coverage), arbitrary sequencing read placement, and fetal DNA fraction on clinically validated NIPT samples.

Study EGAS00001005323

Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future.

Study EGAS00001006839

PGRN-RIKEN: Genetic Determinants of Clinical Cardiovascular Events in Patients Receiving Statins

Coronary heart disease (CHD) is an important public health problem in developed countries. Statins are effective in the prevention and treatment of CHD; nevertheless, many patients receiving statins still suffer cardiovascular events (CV) such as heart attack. Identifying genetic variants responsible for differential clinical responses to statins will not only allow individual patients at high residual risk to be targeted for additional therapies, but also will define new biologic pathways contributing to statin response, and thus new targets for future therapies. Accordingly, the goal of this study is to identify genetic variants associated with clinical CV in patients receiving statins. Subjects identified for study are of European descent and include 1718 subjects with CV while on statins (cases) and 4172 subjects without CV while on statins (controls). Key research resources utilized in this effort include VanderbiltD's BioVU DNA databank and associated Synthetic Derivative database of clinical information, and software tools developed to identify drugs and clinical events using Electronic Health Record-derived structured and unstructured ("free text") data. Most cases and controls identified include three data types: ICD-9 codes, medication regimens, and medical test results. Genotyping, using IlluminaD's Infinium HumanOmniExpressExome BeadChip (OmniExpressExome), was performed by the RIKEN Integrative Medical Sciences Center (IMS) and supported by the Pharmacogenomics Research Network (PGRN)-RIKEN IMS Global Alliance.

Study phs000963

Gut microbiome modulates response to anti PD1 immunotherapy in metastatic melanoma patients

There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R. Metagenomic studies (n=25) revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling demonstrated enhanced systemic and anti-tumor immunity in patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplant from responding patients. Together, these data have important implications for treatment with immune checkpoint blockade in cancer. The fastq files associated with this dataset are stored at ENA under the following accession numbers: PRJEB22894 (Fecal 16S), PRJEB22874 (Oral 16S), PRJEB22895 (Murine 16S), PRJEB22893 (Fecal WGS).

Study EGAS00001002698

Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

Study phs001660

Discover Cancer Image Europe, the first release of the EUCAIM platform to fuel cancer research and data sharing

The EUCAIM consortium and the European Commission have announced the release of Cancer Image Europe, a platform to fuel collaborative innovation and data sharing across Europe. This constitutes a major milestone in EUCAIM's development and an exciting step towards achieving the project's vision and goals. The platform aims to accelerate the pace of AI development and other data-intensive cancer research activities, constituting the basis for a fully-fledged infrastructure for sharing, reusing, and exploiting cancer imaging data, especially using AI techniques. A platform paving the way for the future of cancer diagnosis and treatment Cancer Image Europe brings benefits to researchers, clinicians, and AI innovators across Europe as it addresses the fragmentation of existing cancer image repositories. The platform gathers a public catalogue of cancer imaging datasets from the repositories of the EU-funded AI for Health Imaging projects. A distributed Atlas of Cancer Imaging with over 60 million anonymised cancer image data from over 100,000 patients will be established as part of future updates. The first version of Cancer Image Europe also includes a public catalogue of cancer imaging datasets, a federated searching tool to understand the information available in the federated providers, and full integration with Life Science Login. Moreover, it reuses and adds value to key components of EU-funded research projects and infrastructure in the field of cancer. The Public Catalogue When we talk about data re-use, data discovery is key. The EUCAIM public catalogue is the result of a systematic and collaborative process to which the EGA-CRG has actively contributed. This browsing interface gathers the metadata of the available cancer imaging datasets. This descriptive information will help researchers in their data retrieval. Our contribution to the Public Catalogue comes from our experience gained in the deployment of our federated network, the Federated EGA (FEGA), and as partners in projects such as EuCanImage (AI4HI initiative), in which we worked on the definition of common data models, ontologies and data standards. The EUCAIM Project EUCAIM is a cornerstone of the European Commission-initiated European Cancer Imaging Initiative, a flagship of the Europe's Beating Cancer Plan, which aims to foster innovation and deployment of digital technologies in cancer treatment and care, to achieve more precise and faster clinical decision-making, diagnostics, treatments, and predictive medicine for cancer patients. For more information about the first release of the Cancer Image Europe platform and the EUCAIM project, please visit cancerimage.eu.

Blog discover-cancer-image-europe

Impact of germline pathogenic variants in 27 cancer-predisposing genes on the risk of lymphoma

The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. Sequencing data of controls were obtained from JGAD000721. Germline pathogenic variants in some cancer-predisposing genes were associated with a high risk of lymphoma. Furthermore, germline pathogenic variants in these genes were especially associated with the higher risk of a certain subtype. These results would provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment like other neoplasms.

Study JGAS000347

Microbiomic and immunogenic biomarkers of adjuvant chemotherapy efficacy in stage III colorectal cancer

The standard treatment for stage III colorectal cancer (CRC) is surgery, followed by adjuvant chemotherapy (AC). However, the efficacy of AC is limited, and approximately 30% of patients experience recurrence. Therefore, easily assessable molecular biomarkers that can predict response to AC are needed. Here, we aimed to identify predictive biomarkers of response to AC using tumor transcriptomic data. Tumor specimens from 253 patients who underwent surgery for stage III CRC between 1997 and 2019 were analyzed using RNA sequencing. Transcriptional subtyping and analyses of gut microbiome, immune cell fractions, and T-cell receptor (TCR) were performed to identify factors associated with recurrence-free survival (RFS) in patients treated with or without AC. Of 253 patients, 118 (46.6%) received AC. Twenty phyla and 799 species of the microbiomes were identified, among which Fusobacteria were identified in 247 patients (97.6%). Multivariable Cox proportional hazards regression analysis of patients who received AC showed that intratumoral Fusobacterium and M1 macrophage abundance and diversity of TCR alpha and delta (TRAD) were independently associated with RFS. Fusobacterium and M1 macrophage abundance, and TRAD diversity were associated with the response to AC, suggesting that these factors could serve as biomarkers for personalized treatment in stage III CRC.

Study JGAS000875

CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601

Background. Chordoma is a rare bone tumor with no approved systemic therapy. Inactivation of the tumor suppressor p16 (encoded by CDKN2A) leads to aberrant cyclin D-CDK4/6-RB pathway activity, which can be inhibited by palbociclib in chordoma cell lines. Patients and Methods. We conducted a phase II single-arm, open-labeled trial on palbociclib in adult patients with advanced chordomas with p16 loss (by immunohistochemistry) or CDKN2A loss (by genomic analysis) and CDK4/6 and RB1 presence (by immunohistochemistry or RNA-Sequencing). Patients received 125mg palbociclib once daily for 21 days in a 28-day cycle. The study used a Simon optimal 2-stage design. The primary endpoint was disease control rate after six cycles. Response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included progression-free survival, overall survival, and biomarker analysis. The study was considered positive if 25% of patients reached the primary endpoint. Results. Between December 2017 and April 2023, 28 patients (median age 60 years, range 31-84) were enrolled. After a median follow-up of 28 months, the disease control rate was 39%, with 11 out of 28 patients achieving stable disease. No objective responses were observed. The median progression-free survival was 5.6 months, and the median overall survival was 24.6 months. Treatment was well tolerated without new safety signals. CDKN2A deletions were the most common genomic alterations underlying p16 loss and were accompanied by MTAP co-deletion. There was no correlation between responder phenotypes by immunohistochemistry and outcome. RNA-based analysis showed heterogeneous pathways deregulation at study entry suggesting underlying primary resistance mechanisms Conclusion. This trial met its primary endpoint with a 39% disease control rate, though antitumor activity was modest. Molecularly tailored combination therapies should be considered to improve efficacy. (ClinicalTrials.gov number, NCT03110744).

Study EGAS00001007985

ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer - WGS

Whole genome sequencing data related to the publication "ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer." ERBB2 alterations, usually amplifications or activating mutations, are seen in up to 20% of urothelial carcinoma and can be targeted by monoclonal antibodies, small molecule inhibitors, and most recently, antibody-drug conjugates. Here, we perform targeted and whole-genome sequencing of cell-free DNA and archival FFPE of mUC with and without ERBB2 alterations to identify unique genomic and clinical features of ERBB2-altered cancers, accompanied by IHC, FISH, and detailed clinical outcomes.

Study EGAS50000001082

ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer - Targeted

Targeted sequencing data related to the publication titled "ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer." ERBB2 alterations, usually amplifications or activating mutations, are seen in up to 20% of urothelial carcinoma and can be targeted by monoclonal antibodies, small molecule inhibitors, and most recently, antibody-drug conjugates. Here, we perform targeted and whole-genome sequencing of cell-free DNA and archival FFPE of mUC with and without ERBB2 alterations to identify unique genomic and clinical features of ERBB2-altered cancers, accompanied by IHC, FISH, and detailed clinical outcomes.

Study EGAS50000001081

Covid19 WGS BAM files

The Samples were collected from Saint James's Hospital, Dublin, and after informed consent Extracted Genomic DNA samples were prepared and sequenced using the Automated Illumina TruSeq PCR-free methodology.

Study EGAS00001007048

cell-free methylated DNA immunoprecipitation and high-throughput sequencing data for samples from liver transplant recpients with graft pathologies

Bam and indexed bam files after removal of duplicates and trimming of the unique molecular identifiers. Sequencing was performed on NovaSeq 6000 platform.

Dataset EGAD00001010305

Long-read sequencing for cell-free DNA analysis (human)

31 pregnant women at different trimesters, 6 hepatitis B carriers, and 8 patients with hepatocellular carcinoma

Dataset EGAD00001008980

Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.

The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We investigate the similarity of the tumor microenvironment of 192 local metastatic lesions in 61 ovarian cancer patients. An ecologically inspired measure of microenvironmental diversity derived from multiple metastasis sites is correlated with clinicopathological characteristics and prognostic outcome. We demonstrate a high accuracy of our automated analysis across multiple sites. A low level of similarity in microenvironmental composition is observed between ovary tumor and corresponding local metastases (stromal ratio r = 0.30, lymphocyte ratio r = 0.37). We identify a new measure of microenvironmental diversity derived from Shannon entropy that is highly predictive of poor overall (p = 0.002, HR = 3.18, 95% CI = 1.51-6.68) and progression-free survival (p = 0.0036, HR = 2.83, 95% CI = 1.41-5.7), independent of and stronger than clinical variables, subtype stratifications based on single cell types alone and number of sites. Although stromal influence in ovary tumors is known to have significant clinical implications, our findings reveal an even stronger impact orchestrated by diverse cell types. Quantitative histology-based measures can further enable objective selection of patients who are in urgent need of new therapeutic strategies such as combinatorial treatments targeting heterogeneous tumor microenvironment.

Study EGAS00001002065

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

Neo-RT sWGS

Paired plasma cell-free DNA (cfDNA) samples were collected from 11 breast cancer patients before and after radiotherapy. Sequencing libraries were prepared using the Agilent SureSelect XT HS2 kit and sequenced on the Illumina NovaSeq 6000 platform. Neo-RT (NCT03818100) is a non-randomised, single-arm feasibility study evaluating neoadjuvant radiotherapy combined with endocrine therapy in women with ER-positive, HER2-negative breast cancer. Eligible patients had grade 1 or 2 disease (grade 3 permitted if chemotherapy was contraindicated) and a palpable tumour size ≥20 mm, for whom radiotherapy was intended to facilitate breast-conserving surgery.

Dataset EGAD50000002238

MethCORR: DNA Methylation-based Characterization, Classification and Prognostication of Colorectal Cancer using Archival Formalin-fixed, Paraffin-embedded Tissue

Transcriptional characterization and classification has potential to resolve the inter-tumor heterogeneity of colorectal cancer (CRC) and improve patient management. Yet, robust transcriptional profiling is difficult using formalin-fixed, paraffin-embedded (FFPE) samples, which complicates testing in clinical and archival material. We present MethCORR, an approach that allows uniform molecular characterization and classification of fresh-frozen and FFPE samples. MethCORR identifies genome-wide correlations between RNA expression and DNA methylation in fresh-frozen samples. This information is used to infer gene expression information in FFPE samples from their DNA methylation profiles. MethCORR was applied to methylation profiles from 877 fresh-frozen and FFPE samples and comparative analysis identified the same two major subtypes in four independent cohorts. Furthermore, subtype-specific prognostic biomarkers that better predicted relapse-free survival (HR=2.66, 95% CI [1.67-4.22], P<0.001) than TNM staging and MSI status were identified and validated using DNA methylation-specific PCR assays. The MethCORR approach is general, and may be similarly successful for other cancer types.

Study EGAS00001004293

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+)

We analysed DNA methylation at >850,000 CpG sites across the genome using the Illumina EPIC array in a total of 1,254 cervical liquid-based cytology samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). We developed the WID-CIN-test which is a DNA methylation signature consisting of 5,000 CpG sites.

Study EGAS00001005078

Alzheimer's Disease Sequencing Project (ADSP)

NOTICE OF CHANGE IN LOCATION FOR ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) GENETIC AND PHENOTYPIC DATA: ADSP whole exome and whole genome sequence data that are shared through dbGaP were mapped to the Genome Reference Consortium human genome GRCh37 (build 37). These data are from the Discovery Phase of the project (described below) and will continue to be available at this site. Please see the ADSP Design page for the complete study description. All data that are mapped to GRCh38 (hg38) are being shared through the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service (DSS). For instructions on how access the ADSP Build 38 data that are shared through NIAGADS DSS, visit the Application Instructions page. STUDY DESCRIPTION FOR dbGaP BUILD 37 ADSP DATA: The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genomic variants contributing to increased risk of developing Alzheimer's Disease (AD), (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. These factors will be studied in multi-ethnic populations in order to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. Using existing samples from NIH funded and other studies, three NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC) - Broad, Baylor, and Washington University - produced the DNA sequence data. Variant call data are being made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Analysis of ADSP data will be done in two phases. The Discovery Phase analysis (2014-2018) is funded under PAR-12-183. The entire Discovery dataset contains whole-genome sequencing data on 584 subjects from 113 families, and pedigree data for > 4000 subjects; whole exome sequencing data on 5096 cases 4965 controls; and whole exome sequence data on an additional 853 (682 Cases [510 Non-Hispanic, 172 Hispanic]), and 171 Hispanic Control subjects from families that are multiply affected with AD. The Replication Phase (2016-2021) analysis will be funded under RFA-AG-16-001 and RFA-AG-16-002 and is expected to include a combination of genotyping and sequencing approaches on at least 30,000 subjects. Targeted sequencing will be done by the LSACs. GRCh37 Data Releases The first ADSP data release occurred on November 25, 2013. It included the whole-genome sequencing data in BAM file format on 410 individuals. The second ADSP data release occurred on March 31, 2014, and included the whole-genome sequencing data in BAM file format for an additional 168 individuals. The third ADSP data release occurred on November 03, 2014 and included whole-exome sequencing data in BAM file format for 10,939 individuals. The fourth ADSP data release occurred on February 13, 2015 and included revised ethnic data for subjects with whole-exome sequencing data. The fifth ADSP data release occurred on July 13, 2015 and included whole-genome genotypes and updated phenotypes as well as changes to pedigree structures and sample IDs. The sixth ADSP data release occurred on December 8, 2015, and included whole-exome genotypes and updated phenotypes as well as changes to subject IDs. This seventh ADSP data release on April 12, 2016 includes: (1) WES and WGS SNV VCF files (2) WES and WGS Indel PLINK files ADSP Data Available through dbGaP: ADSP - Whole Genome Sequencing ADSP - Whole Exome Sequencing Comments DNA-Seq (BAM) n=578 n=10913 Sequence data available (plus n=38 replications w/out genotype data) Concordant SNV Genotypes (PLINK format) N/A n=10913 QC'ed genotypes that are concordant between the Atlas (Baylor's) and GATK (Broad's) calling pipelines (a subset of the consensus genotype set) Consensus Genotypes (PLINK and VCF format) n=578 n=10913 QC'ed genotypes that are concordant between Atlas and GATK pipelines as well as those that that were called uniquely by Atlas or GATK Concordant Indel Genotypes (PLINK format) n=578 n=10913 QC'ed genotypes that are concordant between the Atlas and GATK calling pipelines Phenotype Data n=4735 n=10913 Data of n=53 phenotype variables available (plus administrative data), including APOE genotype. WGS phenotypes include data of connecting family members. Please use the release notes provided by dbGaP to obtain detailed information about study release updates. The ADSP data portal provides a customized interface for users to quickly identify and retrieve files by covariates, phenotypes, and data properties such as sequencing facility or coverage. For more information about the ADSP study and the data portal, please visit https://www.niagads.org/adsp/.

Study phs000572

De novo mutations in cell-free foetal DNA - Pulldown experiment

A pulldown experiment with Agilent SureSelect probes designed on regions that were more likely to contain de novo mutations. 266 candidate sites were selected based on whole genome sequencing data. The probes also included the exons of genes that have been identified as neurodevelopmental disorder genes in DDD (the DDG2P genes) 1,336 targets. In addition, the design included the standard iPLEX sites.

Dataset EGAD00001002265

Circulating Tumor DNA Analysis Profiles of Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

The dataset contains circulating tumor DNA (ctDNA) profiles from frozen plasma samples of 593 patients from the TRIDENT-1 clinical trial. Plasma was processed with centrifugation and automated liquid handling systems, and cell-free DNA was extracted using the Qiagen QIAsymphony platform. ctDNA libraries were constructed with the Guardant360 2.11 assay, which used targeted, hybridization-based capture and barcoding of cfDNA fragments for digital analysis, followed by high-throughput sequencing on the Illumina NextSeq 550 instrument. Sequencing data were processed and interpreted using the Bioinformatics Pipeline (BIP v3.5.2 or later) for variant calling and quantification and managed within LabVantage LIMS (v3.7 or later) to support sample tracking and workflow integration. Aligned read files are provided in bam and bai formats.

Dataset EGAD50000002249

Whole-Genome Sequencing of a Healthy Aging Cohort.

Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors.

Study EGAS00001002306

Comprehensive Genomic and Transcriptomic Analysis of Rare Cancers for Guiding of Therapy (H021)

Here we analyzed the molecular profiles and clinical outcomes of 1,310 patients (proportion of rare cancers, 75%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. Based on 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved response and disease control rates (23.9% and 55.3%, respectively) compared to previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients.

Study EGAS00001004813

ENCORAFENIB COMBINED WITH BINIMETINIB FOR BRAFV600E-MUTATED RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE PHASE II GMMG-BIRMA TRIAL (Hipo_K08K)

Activating BRAF mutations are rare events in multiple myeloma but have been shown to be promising therapeutic targets in small case studies. This multicenter phase II trial assessed the efficacy and safety of the BRAF/MEK inhibitors, encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying an activating BRAFV600E mutation. Twelve RRMM patients with a median of five prior lines of therapy were enrolled. The study met its primary endpoint with 10 patients achieving at least a partial response according to IMWG criteria (overall response rate 83.3%). Responses occurred rapidly within the first cycle and deepened over time. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Genomic profiling revealed RAS mutations and structural variants involving the BRAF locus to be drivers of resistance to BRAF/MEK inhibition in RRMM. This trial demonstrates the value of translationally driven clinical trials in selected patient populations.

Study EGAS00001005973

Germline whole genome sequencing of patients with Li-Fraumeni syndrome

Five hundred ng to 1 ug of genomic DNA was submitted to The Centre for Applied Genomics (TCAG) at The Hospital for Sick Children for genomic library preparation and whole genome sequencing. DNA samples were quantified using the Qubit High Sensitivity Assay and purity was assessed using the Nanodrop OD 260/280 ratio. Approximately 500-700 ng of DNA was used as input material for library preparation using the Illumina TruSeq PCR-free DNA Library Prep Kit following the manufacturer’s recommended protocol. In brief, DNA was fragmented to 400 bp on average using sonication on a Covaris LE220 instrument. Fragmented DNA was end-repaired, A-tailed and indexed TruSeq Illumina adapters with overhang-T were added to the DNA. Libraries were then validated on a Bioanalyzer DNA High Sensitivity chip to check for size and absence of primer dimers and quantified by qPCR using Kapa Library Quantification Illumina/ABI Prism Kit protocol (KAPA Biosystems). Validated libraries were pooled in equimolar quantities and paired-end sequenced on an Illumina HiSeq X platform following Illumina’s recommended protocol to generate paired-end reads of 150-bases in length and an average depth of 40X. FASTQ files were aligned to the hg19 reference genome using BWA-mem v0.78. PCR duplicates were marked with Picard MarkDuplicates v1.1.08, and base recalibration and realignment was performed using GATK v2.8.1.

Study EGAS00001007061

An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup

Effective treatment of diffuse large B cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in an R-CHOP-treated DLBCL cohort to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA-seq data revealed novel deletions in RCOR1 to be associated with unfavorable progression free survival (P = 0.001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising of 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (OS) (P = 0.023). The prognostic significance of the 233-gene signature for OS was reproduced in an independent cohort comprising of 195 R- CHOP treated patients (P = 0.039). Additionally, we discovered that within the IPI low risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. Taken together, we present a novel and reproducible molecular subgroup of DLBCL, impacting risk-stratification of R- CHOP treated DLBCL patients and revealing a new avenue for therapeutic intervention strategies.

Study EGAS00001001000

Covid19 WGS Raw Read files

The Samples were collected from Saint James's Hospital, Dublin and after informed consent Extracted Genomic DNA samples were prepared and sequenced using the Automated Illumina TruSeq PCR-free methodology.

Study EGAS00001007106

Tumor Fraction Guided Cell-Free DNA Profiling in Metastatic Cancer Patients

Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. The results show that cfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.

Study phs002290

Whole-genome sequencing of endometrial cancer plasma circulating DNA

This dataset contains whole-genome sequencing data generated from plasma cell-free DNA of dMMR endometrial cancer patients. Sequencing was performed on Illumina platforms to an average depth of approximately 10× and the dataset includes raw sequencing reads in FASTQ format.

Dataset EGAD50000002263

HEMa_LP

This dataset contain WGBS sequencing result of HEMa_LP. The cells were cultured in Medium 254 supplemented with PMA-Free Human Melanocyte Growth Supplement-2 (HMGS-2) under 37°C,5% CO2.

Dataset EGAD00001005486

FASTQ files of total RNA-Seq data from the POPS SGA (Small for Gestational Age) samples

All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

Dataset EGAD00001003507

GnRH Agonist-Induced Ovarian Suppression and Ovarian Steroids in PMDD and Controls

In this study, lymphoblastoid cell line cultures (LCLs) from women with premenstrual dysphoric disorder (PMDD) and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and after estradiol and progesterone treatment. In untreated LCLs, pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) with significant overexpression of MTF2, PHF19, and SIRT1 (P<0.05) in cells from women with PMDD compared with controls. Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs.

Study phs001344

NHLBI TOPMed: The Cleveland Family Study (CFS)

The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont. 994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families. 298 individuals were sequenced as part of TOPMed Phase 3.5, including 169 African-Americans and 129 European-Americans. Among the newly sequenced individuals, 33 were probands with diagnosed sleep apnea, an additional 214 were members of families with probands, and 51 were from neighborhood control families. Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.

Study phs000954

Transcriptomic subgroups in soft tissue tumors correlate with morphologic subtype, genomic features, and outcome

We assessed gene expression (GGE) profiles and gene fusions as detected by transcriptome sequencing (RNA-seq) of 704 soft tissue tumors (STT) representing 56 different tumor types. Comparison with follow-up data identified transcriptional subclusters among sarcomas with complex genomes and among adipocytic tumors that correlated with metastasis-free survival and local recurrences, respectively. Thus, RNA-seq analysis of STT provides clinically important information.

Study EGAS50000001472

Immune and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 trials

The identification of prognostic drivers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigated the complexity of B and T cell receptor (BCR and TCR) repertoires, reflecting antigen-specific immune response, in the context of two phase III trials, namely NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women affected by HER2-positive breast cancer. BCR/TCR features were heterogeneous, and BCR measures describing clonal expansion demonstrated independent prognostic value. A model developed in NeoALTTO and validated in CALGB 40601 predicted event-free survival (EFS) by integrating hormone receptor and clinical nodal status, treatment response (breast pCR)breast pathological complete response (pCR) as well as tumor-infiltrating lymphocytes and BCR evenness, measuring the equality of BCR clonal distribution. The HER2-EveNT score derived from the model allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Study EGAS00001007563

Examination of Engineered LINE-1 Integration Events in HeLa Cells

Long Interspsesed Element-1 (LINE1 or L1) encodes two proteins (ORF1p and ORF2p) required for its mobilization (i.e. retrotransposition) in the human genome. Human ORF2p, a 150kDa protein, has endonuclease (EN) and reverse transcriptase (RT) activities. L1 EN is classified as apurinic/apyrimidin-like endonuclease (APE) and is responsible for initiating target-site primer reverse transcription (TPRT) during the L1 retrotransposition cycle. During canonical TPRT, the L1 EN activity makes a single-strand endonucleolytic nick at a double-strand DNA target sequence in genomic DNA. The endonucleolytic nick is typically made at an L1 EN degnerate consensus cleavage sequence (5'-TTTT/A-3') exposing a free 3' hydroxy group that can be used as a primer by the ORF2p L1 RT activity to reverse transcribe the associated L1 RNA. Here, we characterized over 21,000 de novo engineered L1 retrotransposition events in HeLa cells to determine if L1 exhibits overt integration preferences in the human genome. Bru-seq of HeLa cells to determine actively transcribed regions of the genome was also performed. This Bru-seq data was used to determine if engineered L1 integration events preferentially integrate into transcribed regions of the genome, and to determine which strand during transcription may present itself as preferential during L1 retrotransposition.

Study phs001669

Longitudinal copy number variation analysis from plasma DNA of head and neck cancer patients under re-radiotherapy

Recurrent locally advanced head and neck cancer (HNC) patients, receiving re-radiotherapy (re-RT), are presented with short progression-free (PFS) and overall survival. Hence, biomarkers predicting therapy failure are urgently needed. We analyzed copy number variations (CNVs) in blood plasma of HNC patients collected before, during and after re-RT. Detectable CNVs after five and ten fractions of re-irradiation as well as at the end of re-RT were associated with short PFS. Furthermore, we found that CNV kinetics in longitudinally collected plasma reflected therapy response and could detect disease progression in advance of radiographic tumor assessments.

Study EGAS50000000163

Rapid response of APC/TP53/KRAS mutated stage IV colorectal cancer under FOLFIRI + Bevacizumab detected by liquid biopsy: a case report

In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle,

Study EGAS00001004088

Clinal phenotype dataset

Clinical data from IMvigor010: Clinical data include race, sex, baseline ecog, tumor stage, node status, prior neoadjuvant, PD-L1 status, number lymph nodes resected, pridis, arm, overall survival and disease free survival for 809 patients across IMvigor010.

Dataset EGAD00001007576

Sequence data from stage I of the CCTG BR.36 ctDNA-directed, multi-center phase II study of molecular response adaptive immunotherapy in non-small cell lung cancer

The dataset for the study "Early ctDNA molecular response captures therapeutic response in the first stage of CCTG BR.36 ctDNA-directed, multi-center phase II study of molecular response adaptive immunotherapy in non-small cell lung cancer", includes 134 bam files from hybrid capture targeted error-correction next-generation sequencing (PGDx Elio plasma resolve) from plasma cell-free DNA and matched white blood cell DNA from 35 individuals with non-small cell lung cancer on the BR.36 trial, alongside 11 bam files from targeted next generation sequencing (PGDx Elio tissue complete) of tumor DNA from 11 individuals with non-small cell lung cancer on the BR.36 trial.

Dataset EGAD00001011359

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

Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals

This study presents a methodology for detecting circulating tumor DNA (ctDNA) using deep whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive alternative to bisulphite sequencing. The method enables simultaneous analysis of genomic and methylomic data for multi-cancer detection and monitoring minimal residual disease. In a diagnostic accuracy study across various cancer types, it achieved 85.3% sensitivity and 88.8% specificity, with validation done using matched tumour biopsies. Additionally, in silico validation showed strong discrimination at low ctDNA levels. The approach also successfully tracks tumour burden and ctDNA shedding from precancerous lesions post-treatment, making it ready for further clinical testing.

Study EGAS50000000715

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