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• Methylome sequencing of cell-free DNA and RRBS of solid tissue

  Early cancer detection by cell-free DNA (cfDNA) faces multiple challenges: low fraction of tumor cfDNA, molecular heterogeneity of cancer, and sample sizes not sufficient to reflect diverse patient population. We develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of cfDNA methylome (with >12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our system to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, thereby permitting the classification models to learn new features as training cohorts grow, and expanding their scope to other cancer types.

  Study EGAS00001006020

• The effect of pre-analytical and physiological variables on cell-free DNA fragmentation

  Background: assays that account for the biological properties and fragmentation of cell-free DNA (cfDNA) can improve the performance of liquid biopsy. However, pre-analytic and physiological differences between individuals on fragmentomic analysis are poorly defined. Methods: we analyzed the impact of collection tube, plasma processing time and physiology on the size distribution of cfDNA, their genome-wide representation and sequence diversity at the cfDNA fragment-ends using shallow Whole Genome Sequencing. Results: we observed that using different stabilizing collection tubes, or processing times does not affect the cfDNA fragment sizes, but can impact the genome-wide fragmentation patterns and fragment-end sequences of cfDNA. In addition, beyond differences depending on the gender, the physiological conditions tested between 63 individuals (age, body mass index, use of medication and chronic conditions) minimally influenced the outcome of fragmentomic methods. Conclusions: our results highlight that fragmentomic approaches have potential for implementation in the clinic, pending clear traceability of analytical and physiological factors.

  Study EGAS00001005748

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• Joint-Specific TF Regulation in RA

  The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated bulk, whole-genome transcriptomic and chromatin accessibility data from FLS. Samples were matched in age, sex, and were homogeneous in that all had significant joint damage with longstanding disease requiring surgical intervention. Analysis revealed joint-specific patterns of FLS phenotypes, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an ‘activated' state relative to the ‘resting' state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

  Study phs003633

• A mathematical model of cell-free DNA fragment size reveals cancer-specific fragmentomic patterns

  This study aim to test a mathematical model of cfDNA length distribution across multiple biodiy flulids. It try to investigate biological mechanisms of cfDNA fragmentation and release.

  Study EGAS50000001560

• Paired FastQ files from deep targeted DNA sequencing

  This dataset comprises paired-end and time-matched FastQ files from 356 cell-free DNA samples and 356 white blood cell DNA samples, derived from 299 patients with metastatic renal cell carcinoma or urothelial carcinoma. A baseline sample was available for all patients. Sequencing was performed using Illumina technology.

  Dataset EGAD50000001267

• IMpower133 (GO30081) clinical data and biomarker data

  Relevant clinical data for IMpower133 (GO30081) including treatment arm, overall survival, progression-free survival, best overall response, PD-L1 IHC, molecular subtype, and baseline clinical features.

  Dataset EGAD50000000195

• DNA methylation-based classification of sinonasal tumors [Proteomics data]

  This dataset includes raw label-free mass spectrometry proteomics data of different sinonasal tumor entities as well as normal sinonasal tissue. 72 samples were processed on a Q Exactive HF-X instrument coupled to an easy nanoLC 1200 system using one microgram of peptides and an 110 minutes gradient.

  Dataset EGAD00010002381

• Dynamics of multiple resistance mechanisms in plasma DNA and their clinical implications for NSCLC patients receiving EGFR-targeted therapies

  Background:The development of resistance mechanisms to targeted therapies is complicated by underlying tumour heterogeneity. When multiple resistance mechanisms co-exist, identifying the dominant driver(s) is critical for selection of treatment. Patients and methods:We studied the relative dynamics of multiple oncogenic drivers and resistance mechanisms in 50 patients with EGFR-mutant non-small cell lung cancer (NSCLC), during treatment with gefitinib and hydroxychloroquine (NCT00809237). We performed digital PCR and targeted deep sequencing of cell-free DNA from longitudinal plasma samples from all patients, and shallow whole genome sequencing of serial samples from three patients who underwent histological transformation to small-cell lung cancer (SCLC). ResultsEGFR activating mutations were assessed in tumour samples and accurately identified in plasma samples of 95% of patients (41/43). We identified additional mutations including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%), and PTEN (4/50, 8%), and tracked their relative levels in plasma. Patients with both TP53 and EGFR mutations detected in plasma pre-treatment tended to have worse overall survival than those where only EGFR was detected. The resistance-conferring EGFR T790M mutation was identified in 62% of the patients who progressed. Changes in relative levels of T790M and activating mutations in EGFR corresponded to clinical responses in two patients who were given sequential treatments. Patients who progressed without T790M detected in plasma had worse PFS during TKI continuation, and developed alternative resistance mechanisms, that could be identified in plasma DNA, including SCLC-associated copy number changes and TP53 mutations, that tracked with progression and response to subsequent therapies. Conclusion:Longitudinal analysis of multiple oncogenic drivers in ctDNA may help identifying dominant mechanisms of resistance to EGFR-targeted therapies, and highlight the importance of monitoring genetic events that are not direct drug targets but provide non-invasive molecular information that may guide clinical management.

  Study EGAS00001002908

• 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

• ctDNA to predict risk of progression and death after trifluridin/tipiracil therapy

  Background. Late-line treatment in metastatic colorectal cancer (mCRC) can improve the prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. Despite many promising results, the role of circulating tumor DNA (ctDNA) analysis in trifluridin/tipiracil (FTD/TPI) treated mCRC patients is so far still elusive. Study design. This prospective non-interventional translational biomarker phase II study enrolled 30 metastatic CRC patients treated with FTD/TPI. The primary study aim was to identify a molecular biomarker to predict overall survival (OS) benefit upon FTD/TPI treatment. Methods. mCRC patients (60% male, 40% female) with FTD/TPI therapy were included. Molecular profiling in cell-free DNA from plasma was performed prior to treatment and on average 4, 8 and 12 weeks after FTD/TPI initiation. Tumor levels were assessed as the highest variant allele frequency (hVAF) and correlated with OS. Uni- and multivariate analyses for survival were performed with clinical variables. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG performance status. Results. Compared to previous data, our disease control rate of 30% was lower with a median OS of 8.1 months and a median PFS of 3.2 months. At baseline (BL) and the first two follow-ups (FU), a hVAF cut-off of 7.5% was most discriminative (BL HR 0.39 95% CI 0.16 - 0.98 P=0.0212, FU1 HR 0.30 95% CI 0.12 -0.77 P=0.0021, FU2 HR 0.23 95% CI 0.08-0.70 P=0.0004) whereas at the last follow-up the stratification was most pronounced at a 15% cut-off. An elevated hVAF trajectory over time was associated with a higher risk of death. Conclusion. ctDNA is detectable in a high proportion of mCRC patients. Changes in ctDNA levels are associated with survival among FTD/TPI therapy and may identify patients who benefit most from treatment in these late-stage disease.

  Study EGAS00001006883

• Angelman, Rett, Prader-Willi Syndrome Consortium (ARP) Rett Syndrome Natural History Protocol

  This observational study will involve the comprehensive assessment of the clinical features of Rett syndrome with this Rare Diseases Clinical Research Network. A clinical database of 1350 individuals with Rett syndrome including MECP2 mutation status for the purpose of elaborating phenotype-genotype correlations will be established. Eligible participants will be enrolled in the natural history study for 11 years from the 4 clinic sites currently involved with Rett syndrome (BCM, GGC, and UAB, CHB) as well as from the several thousand registrants in the International Rett Syndrome Foundation registry who will be invited to the nearest consortium site involved in Rett syndrome. Potential participants are expected to have had determination of their MECP2 mutation status, but will not be excluded should no mutation be present. All individuals who meet criteria and are currently receiving care from study sites will be invited to participate (N>600). Additional participants will be invited through the assistance of the International Rett Syndrome Foundation (IRSF). All individuals with RS registered with IRSF will be invited to participate in this study via the IRSF website and the IRSF newsletter. Potential participants will be apprised of the participating study sites and invited to contact one of the sites based on feasibility of travel. Inasmuch as the enrollment goal of 1350 participants is 40% of the current IRSF registry, we believe this will be a representative sampling. Bias can certainly occur based on travel requirements, level of interest, and other factors. However, inclusion of such a large sample should minimize sampling bias. No travel expenses will be covered, so it is likely that participants will be those with geographic proximity to Houston, Greenwood, Birmingham, or Boston. From the sample pool described above, the aim is to conduct the observational longitudinal (natural history) study on up to 1350 participants with classic Rett syndrome and variant forms of Rett syndrome, that is, participants who fully meet the established clinical criteria for Rett syndrome and those who meet some but not all of these criteria. All participants expressing MECP2 mutations irrespective of phenotype will be eligible for enrollment. For each of the eight common genetic mutations as well as those with large scale deletions, the prevalence of the following RS characteristics will be estimated for each age category and overall: seizure presence and frequency, ambulation status, scoliosis, ECG abnormality, breathing irregularities while awake, feeding difficulties, growth as measured in percentiles from NCHS standards curves, the presence of osteopenia as evidenced by bone fracture, and the presence of gallbladder disease. Both incidence and prevalence estimates will be made using a combination of data obtained at the regularly scheduled clinical visits and that obtained from the medical history. Incidence estimates will be calculated using time-to-event analyses (e.g., Kaplan-Meier survival curves) with appropriate calculations of standard errors and 95% confidence intervals. Cox proportional hazard regression models will be used to allow control for other factors, and t-tests will be calculated on the coefficients themselves. Appropriate transformations on explanatory variables will be used as deemed necessary in Cox models. Prevalence estimates will be calculated from estimates of proportions with exact confidence intervals. For a sample size of 275, the standard error of the estimate will not exceed 0.03 (3%) and for a sample size of 60, the standard error of the estimate will not exceed 0.06 (6%).

  Study phs000574

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Version 3 (ROC-Cardiac Epistry 3-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. Available Data The ROC Cardiac Epistry version 3 include all cardiac arrest cases entered into the ROC database from April 1, 2011 to June 30, 2015. This is separate from versions 1 and 2 because of the major changes in how and which data were collected. Version 3 represents the following major changes to the structure and data collection: separate ED Arrival and Hospital Admits forms, mandatory ED and Hospital elements and a revamped CPR Process form. For ROC traumatic injury Epistry data please see: ROC-Trauma Epistry Objectives To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest; to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes. Background Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes. Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants There were 120,306 participants. Design ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003726

• The African American Breast Cancer Epidemiology and Risk (AMBER) Consortium Study

  The AMBER Consortium Study was formed to pool interview data, questionnaire data, and biological samples from epidemiological studies of breast cancer in African-American women to discover the potential causes of early-onset and aggressive breast cancer in African-American women. AMBER is funded through a Program Project grant from the National Cancer Institute. Genetic data submitted to dbGaP come from participants in the Carolina Breast Cancer Study, Women's Circle of Health Study, and Black Women's Health Study. The P01 consists of four scientific projects; the aims include follow-up on previous GWAS findings for breast cancer susceptibility in AA women as well as investigation of SNPs in candidate genes in biologically plausible pathways. These SNPs were genotyped using DNA from 3130 African-American women with breast cancer and 3700 controls. Descriptions of the original studies that provided the data and samples for this collaborative study are given below. The Carolina Breast Cancer Study (CBCS): a North Carolina population-based case-control study of breast cancer, conducted in three phases. The current study phase, phase 3 (years 2008-2014), includes women residents in 44 counties. CBCS phases 1 and 2 were conducted in 24 counties. Breast cancer cases are identified using Rapid Case Ascertainment in cooperation with the NC Central Cancer Registry. Controls were identified for phases 1 and 2 only (1993-1996 and 1996-2001), using Division of Motor Vehicles lists for women under age 65 and Health Care Financing Administration lists for women 65 and older. Randomized recruitment was used to oversample AA women and women under age 50. In-depth interviews are conducted by study nurses in participants' homes to obtain information on potential risk factors for breast cancer. DNA samples have been obtained from most participants. Overall response rates for Phases 1 and 2 were 74% for AA cases and 54% for AA controls. Phase 3, conducted in 44 counties from 2008-2014, includes cases only. The response rate for AA cases in Phase 3 was 70.5%. The Women's Circle of Health Study (WCHS): a multi-site case-control study in New York City (NYC) and New Jersey (NJ) aimed at evaluating risk factors for early and aggressive breast cancer in women of AA and EA ancestry. Recruitment in NYC took place between January 2002 and December 2008 and involved hospital-based ascertainment of cases, while controls were identified through random digit dialing (RDD). Recruitment at the NJ site started in March 2006 and is ongoing. Phase I of the study ended in April 2012 and covered seven counties in NJ. WCHS2 includes two additional counties. Cases in NJ were identified from 2006 to 2012 by the NJ State Cancer Registry using rapid case ascertainment. Controls were initially recruited though RDD (2006 to 2010) and later through community-based efforts (2009-2012). In-person interviews ascertained data on established and suspected risk factors for breast cancer. DNA samples were obtained. Among eligible AA women, 75% in NY and 54% in NJ completed an interview and provided a biologic specimen. Black Women's Health Study (BWHS): an ongoing prospective cohort study of health and illness among U.S. black women, with a focus on cancer. The study began in 1995 when 59,000 AA women 21-69 years of age from across the United States completed a 14-page postal health questionnaire. The median age at entry was 38, and participants were residents of 17 states in mainland U.S.: Northeast, 28%; South, 30%; Midwest, 23%; West, 19%. The baseline questionnaire elicited information on a wide range of variables, including demographic factors, use of medical care, family history of breast cancer, reproductive and medical history, cigarette and alcohol use, weight, height, waist and hip circumference, medication use, diet, and exercise. Biennial follow-up questionnaires ascertain new cases of breast cancer and other illnesses and update covariate information. Medical record and cancer registry data are sought for all participants who report a diagnosis of breast cancer. As of 2014, approximately 80% of the baseline cohort have completed follow-up. DNA samples were obtained from about 50% of participants. BWHS data for the AMBER consortium were prepared as a nested case-control study, with controls frequency-matched to cases on year of birth, geographic region, and most recent questionnaire completed prior to the end of the at-risk period.

  Study phs000669

• VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment

  The Vanderbilt Electronic Systems for Pharmacogenomic Assessment (VESPA) Project is a large electronic medical record (EMR)- and biobank-based initiative for translational pharmacogenomics discoveries. Key research resources utilized in this effort include the BioVU DNA databank and associated Synthetic Derivative database of clinical information, and software tools developed to identify drugs and clinical events using EHR-derived structured and unstructured ("free text") data. Cohorts include subjects with primarily drug-response phenotypes, and most cases and controls identified include three data types: ICD-9 codes, medication regimens, and medical test results. Advanced informatics methods, such as natural language processing, were also used for some phenotypes. Algorithms used event-sequence analyses to establish temporal relationships between drugs and phenotypes. Both cases and control algorithms excluded records that contained specific comorbidities and were refined to achieve positive predictive value (PPV) > 90%. For automated algorithms failing to meet this threshold, manual review was coupled with algorithms to validate that the included cases were true positives. A total of 11,639 subjects met phenotyping criteria for a least one of the 28 phenotypes investigated. Across all phenotypes cases and controls, 90% were reused as either a case or control for a least one other phenotype. Data are deposited for individual phenotypes in the VESPA substudies. Substudies: VESPA: Genome Wide Association Study of Serum Creatinine during Vancomycin Therapy and Vancomycin Pharmacokinetics - phs000894 VESPA: Genome Wide Study of Clinically Diagnosed Ace Inhibitor Cough - phs000992

  Study phs000991

• Expression of Activation Induced Cytidine Deaminase and Risk of Transformation in Follicular Lymphoma

  It is currently unclear how to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression. Building on a prior study demonstrating early transformation in FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS1, and MYC, in a more contemporary cohort of 199 newly diagnosed grade 1 and grade 2 FLs using targeted capture and massively parallel sequencing. BCL2 mutations with VAF >20% occurred in 52% of cases. Among 97 FLs that did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF >20% were associated with shorter, event-free survival (EFS, median 1.4 years with these mutations versus 4.5 years without, p = 0.048), and increased risk of transformation (HR 3.01, 95% CI 1.03-8.77, p = 0.04). Other sequenced genes were less frequently mutated and did not significantly increase the prognostic value of the panel. Across the entire population, BCL2 mutations at VAF >20% were associated with decreased EFS (HR 1.58, 95% CI 1.03-2.40, p = 0.034 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.86, 95% CI 1.07-3.23, p = 0.029). Thus, high VAF BCL2 mutations remain a prognostic factor for FL even in the chemoimmunotherapy era and might need to be considered in future study design.

  Study phs002845

• Utility of Capillary Blood in Gene Expression Studies

  The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using capillary blood collected by fingerstick, with the goal of developing practical fingerstick blood collections to expand blood collection capabilities and allow large-scale or field-based collections. We compared the RNA sequencing results obtained from two different capillary blood collection and RNA extraction methods with the results obtained from a standard venous blood collection and RNA extraction protocol. We also compared capillary blood processing methods, as well as fingerstick locations, within one capillary collection/extraction method. Within each method we sought to distinguish male from female participants to assess the capacity of each collection/extraction method for gene expression profiling. The study population included 40 participants aged 18-60 who were free from any acute illness or any illness that would preclude blood collection. We determined that capillary blood possesses large-scale significant differences from venous blood and that the two capillary methods produced similar gene expression profiles. We further determined that all methods were useful for detecting gene expression differences between assessed groups (male and female participants in this case). We conclude that capillary blood is suitable for gene expression profiling in quantities as low as 100 μL whole blood, but recommend that researchers should rely on a single blood collection method if they desire to compare results between individual studies. Raw sequencing files (.fastq) from this study are available in dbGaP.

  Study phs003496

• Illumina HumanCoreExome genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanCoreExome BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotypes were called using GenCall (Illumina Genome Studio) followed by zCall and quality control (QC) was performed in two stages (pre- and post-zCall).

  Study EGAS00001001001

• Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

  Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 yr using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers, to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

  Study EGAS00001003497

• deep-learning-powered tissue deconvolution for cfDNA

  Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.

  Study EGAS00001007213

• Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guérin

  The recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.

  Study EGAS00001006879

• Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's or Parkinson's disease correlate with disease status and features of pathology

  We profiled the miRNA contents from cerebrospinal fluid and serum (using next generation sequencing) from postmortem patients diagnosed with Alzheimer's or Parkinson's disease, and neurologically normal controls. All biofluids were cell-free and patient matched, there was one cerebrospinal fluid and one serum sample from each of 70 patients with Alzheimer's disease, 67 patients with Parkinson's disease and 78 age-similar controls. We correlated the miRNA changes with measurements of neuropathology such as plaques, tangles and Lewy bodies.

  Study phs000727

• A prospective multicenter study of plasma ctDNA versus archival tumor tissue to guide FGFR-targeted therapy in metastatic urothelial cancer - Targeted

  Targeted sequencing data related to the publication titled "A prospective multicenter study of plasma ctDNA versus archival tumor tissue to guide FGFR-targeted therapy in metastatic urothelial cancer." FGFR alterations, seen in up to 25% of metastatic urothelial carcinoma, can be exploited with targeted therapy. Here, we perform targeted sequencing of cell-free DNA, archival FFPE, and white blood cell DNA to compare ctDNA versus tissue for FGFR biomarker status and monitor temporal changes to FGFR over the disease course, specifically after progressing on targeted therapy.

  Study EGAS50000001450

• 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