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• Extended longitudinal single-cell RNA-seq data from ovarian cancer across multiple treatment phases

  The dataset contains single-cell RNA-seq data of 73 tumor samples high-grade serous carcinoma (HGSC) patients sequenced with Novaseq. The samples were collected at primary, interval, and relapse treatment phases from multiple tissue sites. The files provided are fastq files.

  Dataset EGAD50000001855

• Whole genome sequencing

  The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC) is not well understood. We performed whole genome sequencing on primary and metastatic sites from highly clinically annotated HGSC samples. Samples were obtained pre-treatment based on a laparoscopic triage algorithm from patients who underwent R0 tumor debulking, or received neoadjuvant chemotherapy (NACT) with excellent or poor response.

  Dataset EGAD00001005240

• Cell-free DNA Methylome Analysis Enables Early Preeclampsia Prediction

  This dataset contains in solution target-enrichment bisulfite sequencing of placental tissue, buffy coat and plasma DNA from pregnant women. Blood samples were taken for cell-free DNA (cfDNA) DNA extraction from 64 women at the time of early-onset preeclampsia (PE) diagnosis, or from 38 controls (uncomplicated pregnancies) at a similar gestational age that did not develop preeclampsia subsequently. Among these subjects, plasma samples from 7 PE patients and 6 controls were also subjected to oxidative bisulfite sequencing. Placental tissues from 11 PE and 26 control subjects after delivery, and buffy coat from 16 PE and 16 control subjects at the same time of cfDNA sampling were profiled. A discovery cohort for early PE assessment in the first trimester was collected. In this cohort, cfDNA from 75 pregnancies that went on to develop early-onset PE and from 124 matched controls were collected and methylome sequencing were carried out. An independent validation cohort to validate early PE assessment with methylome profiling was collected as well. This validation cohort includes cfDNA samples from 61 PE and 136 control pregnancies.

  Dataset EGAD00001010159

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153

• Immune-Related Adverse Events after Immune Checkpoint Blockade-Based Therapy are Associated with Improved Survival in Advanced Sarcoma

  Immune activation after immune checkpoint blockade (ICB) can lead to a unique group of adverse events (AEs), which have been associated with improved outcome in many carcinomas. The association between immune-related AEs (irAEs) and outcome in patients with sarcoma is not well studied. This study has two components: (1) a retrospective clinical study of irAEs among 131 patients treated with ICB at Memorial Sloan Kettering Cancer Center and (2) an analysis of a subset of these patients who have whole transcriptome sequencing available for analysis. In the clinical study portion, we reviewed a cohort of patients with advanced sarcoma treated on prospective clinical trials utilizing ICB-based therapy between April 2017 and January 2020. The objectives were to pool the safety data from each trial, identify irAEs, and correlate them with best overall response by RECIST 1.1, progression-free survival (PFS) and overall survival (OS). Association of irAEs with response and survival was assessed using a Cox regression model. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one Grade ≥ 3 irAE. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the hazard ratio (HR) for an irAE (HR 0.662, 95% CI 0.421 - 1.041) approached, but did not reach statistical significance for PFS (P = 0.074), while patients had a significantly lower HR for OS (HR 0.443, 95% CI 0.246 – 0.798; P = 0.007) compared to those without or before an irAE. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. In total, 71 unique patients had RNA sequencing available for analysis. The transcriptomes of 31 of these patients have been previously uploaded to dbGaP (phs002852), leaving 36 unique transcriptomes that have not been previously publicly shared. Three patients did not agree for their sequencing to be publicly shared. Therefore, 33 unique patient samples will be uploaded to this dbGaP study. Overall, this study found that gene expression profiling on baseline tumor samples from patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways.

  Study phs003284

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• Non-viral precision T cell receptor replacement for personalized cell therapy

  The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognizing mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.

  Study EGAS00001006898

• SPECTA: NGS Screening Program for Efficient Clinical Trial Access

  SPECTA comprises a network of participating European clinical sites and NGS screening platforms that can screen individual patients for multiple molecular targets and potentially allow the design of trials that will match the specific biology of the diseases affecting specific patients with cancer.

  Dataset EGAD00001000894

• The Genetic Basis of Progression in Multiple Sclerosis

  This study examined the genetic determinants of multiple sclerosis (MS) severity in an international cohort of people with MS assembled by the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium. A total of 12,584 people with MS of European ancestry were included in the main genome-wide association study (GWAS). Participants were enriched for older individuals with longer disease duration (mean age 51.7 years and mean disease duration 18.2 years). All individuals were whole-genome genotyped on the Illumina Global Screen Array (GSAMD-24v2-0). Imputation was performed using the Haplotype Reference Consortium reference panel. The primary outcome was the age-related MS severity score. All individuals had at least 1 expanded disability status scale (EDSS) measure. When multiple EDSS scores were available, the last one was selected to calculate the age-related MS severity score.Of those 12,584 people with MS, this data release includes 4,623 participants recruited from non-European sites in the US, Canada and Australia. This release includes individual-level genotype and phenotype files necessary to replicate our GWAS of MS severity, including covariates.

  Study phs002929

• CPTAC: Molecular Dissection of Chemotherapy Response in Triple Negative Breast Cancer

  Sporadic Triple Negative Breast Cancer (TNBC) represents 10-15% of breast cancers (BC) worldwide. Non-specific chemotherapy remains the standard of care as there are no targeted agents. In 50% of cases, pathological complete response (pCR) is not achieved, and these individuals experience poor survival. Predictive markers for chemotherapy have proved elusive, and patients can receive up to five different chemotherapy agents to optimize outcomes. Microscaled proteogenomics (PMID: 31988290) is a discovery technique that integrates DNA and RNA sequencing with mass spectrometry based proteomics. This approach was applied to snap-frozen biopsies obtained before TNBC treatment on a clinical trial of carboplatin and docetaxel. Proteogenomic profiling included whole exome sequencing (WES), RNA-seq, and tandem mass tag based proteomics and phosphoproteomics.The study was approved by the IRB at both participating sites: Washington University in St. Louis and Baylor College of Medicine (BCM), and followed the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol and informed consent documents were approved by Washington University School of Medicine (WUSM) and BCM.

  Study phs002505