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• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• High-depth whole genome sequencing of 26 premalignant breast lesions

  Ductal carcinoma in situ (DCIS) is a non-obligate precursor lesion of breast cancer, representing 20-25% of newly diagnosed breast cancer lesions. It is currently not possible to predict which DCIS patients will progress to invasive breast cancer. The samples deposited here are part of a larger study using high-depth whole-genome sequencing (WGS) to investigate the somatic mutation genomic landscape of DCIS. Comprehensive evaluation of DCIS genomes aims to uncover biological insights into breast cancer progression and potential opportunities to stratify DCIS patients for personalised treatment options or active surveillance. Due to specific restrictions imposed by the ethical approval at sample collection, the use of the germline data is restricted to filtering of somatic mutation calls only and cannot be used outside this purpose.

  Study EGAS50000001559

• Genomic Sequencing of Cervical Cancers

  Cervical cancer is responsible for 10-15% of cancer related deaths in women worldwide. The etiological role of infection with high-risk human papilloma viruses (HPV) in carcinomas of the cervix is well established. In general, the development of cervical carcinomas follows a progression from persistent HPV infection through precancerous lesions to invasive cancer. Previous studies have implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as chromosome-arm level copy number alterations in the pathogenesis of cervical carcinomas. Here, we report whole exome sequencing analysis of 118 cervical carcinoma-normal paired samples from patients in Norway and Mexico, as well as transcriptome sequencing of 80 cases and whole genome sequencing of 13 tumor-normal pairs. Novel somatic mutations include recurrent E322K substitutions in the MAPK1 gene encoding the ERK2 kinase and inactivating mutations in the HLA-B gene. In addition, recurrent somatic mutations in FBXW7, EP300, and NFE2L2 are novel in the context of primary cervical carcinomas. Analysis of HPV integration sites revealed recurrent integration into the RAD51B locus as well as co-occurrence of HPV genome integration and copy number gains within several genomic loci. These findings shed new light on the pathogenesis of cervical carcinomas and suggest potential novel therapeutic targets.

  Study phs000600

• Sclerosing epithelioid fibrosarcoma case report

  Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft tissue sarcomathought to originate in fibroblasts of the tissues surrounding tendons, ligaments and muscles. Minimally responsive to conventional cytotoxic chemotherapies, greater than 50% of SEF patients experience relapse and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-year-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. The patient described in this report experienced persistent disease progression despite being heavily treated with multiple surgeries, radiation, numerous chemotherapies and targeted therapeutics. Primary tumor, metastatic and relapse sites were sequenced by whole genome, whole exome, and deep transcriptome next generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1-CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and a discussion as to potential therapeutic strategies for SEF.

  Study EGAS00001005214

• CancerDetector: Ultrasensitive and Non-Invasive Cancer Detection at the Resolution of Individual Reads using Cell-free DNA Methylation Sequencing Data

  The detection of tumor-derived cell-free DNA in plasma is one of the most promising directions in cancer diagnosis. The major challenge in such approach is how to identify the tiny amount of tumor DNAs out of total cell-free DNAs in blood. Here we propose an ultrasensitive cancer detection method, termed “CancerDetector”, using the DNA methylation profiles of cell-free DNAs. The key of our method is to probabilistically model the joint methylation patterns of multiple adjacent CpG sites on an individual sequencing read, in order to exploit the pervasive nature of DNA methylation for signal amplification. Therefore, CancerDetector can sensitively identify a trace amount of tumor cfDNAs in plasma, at the level of individual reads. We evaluated CancerDetector on the simulated data, and showed a high concordance of the predicted and true tumor burden. Testing CancerDetector on real plasma data demonstrated its high sensitivity and specificity in detecting tumor DNAs. In addition, the predicted tumor burden showed great consistency with tumor size and survival outcome. Note that all of those testing were performed on sequencing data at low to medium coverage (1X to 10X). Therefore, CancerDetector holds the great potential to detect cancer early and cost-effectively.

  Study EGAS00001002728

• Sclerosing epithelioid fibrosarcoma case report

  Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft tissue sarcomathought to originate in fibroblasts of the tissues surrounding tendons, ligaments and muscles. Minimally responsive to conventional cytotoxic chemotherapies, greater than 50% of SEF patients experience relapse and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-year-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. The patient described in this report experienced persistent disease progression despite being heavily treated with multiple surgeries, radiation, numerous chemotherapies and targeted therapeutics. Primary tumor, metastatic and relapse sites were sequenced by whole genome, whole exome, and deep transcriptome next generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1-CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and a discussion as to potential therapeutic strategies for SEF.

  Study EGAS00001005215

• Single-Cell Mitochondrial Mutation Lineage Tracing of Non-Dysplastic and Dysplastic Barrett's Esophagus

  This study addresses a critical knowledge gap in understanding Barrett's esophagus (BE), a common metaplastic condition and precursor to esophageal adenocarcinoma, by identifying lineage connections and cell states underlying its development and malignant transformation. We collected biopsies from 13 Barrett's esophagus patients undergoing routine surveillance endoscopy, sampling metaplastic tissue alongside normal squamous esophagus and gastric cardia tissues when clinically appropriate. Our novel approach integrated single-cell RNA sequencing of nearly 180,000 cells with mitochondrial DNA mutation analysis for lineage tracing, coupled with spatial transcriptomics and comprehensive whole-exome sequencing. For one patient with high-grade dysplasia, we performed detailed whole-exome sequencing analysis at 100x coverage on dissociated Barrett's esophagus cells alongside matched normal esophagus and gastric cardia tissues. This genomic profiling revealed critical genetic drivers of malignant transformation, including a truncating mutation in the mutation cluster region of APC (a negative WNT regulator), mutations in the tumor suppressor genes CDKN2A and TP53, and significant copy number alterations including loss of CDKN2A on chromosome 9. These genetic alterations corresponded with the transcriptional changes observed in our single-cell data, particularly WNT pathway dysregulation and the expansion of LGR5-expressing stem cells, providing molecular evidence for how single clones can initiate the dysplastic transformation. Data deposited in dbGaP consist specifically of the whole-exome sequencing raw files, processed variant calls, and copy number analyses from the single patient with high-grade dysplasia and matched normal esophagus and stomach control tissue. Whole exome sequencing was performed on an Illumina NovaSeq 6000. Sequencing data was preprocessed following the Genome Analysis Toolkit's (GATK) Best Practices. Sequencing data was analyzed with Mutect2 (GATK, v4.2.5.0) to identify short somatic mutations including single-nucleotide polymorphisms and insertions and deletions. The Barrett's esophagus sample was run with the two matched normals, as well as the publicly available germline resource somatic-hg38_af-only-gnomad.hg38.vcf.gz (GATK). Somatic variant calls were filtered using FilterMutectCalls (GATK) and loaded into the Integrative Genomics Viewer (v2.12.3) for identification of high-quality variants in known esophageal adenocarcinoma regulators. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9). CNV, Mutect2, and SVC analyses will be made available through dbGAP. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9) with the default run settings; a pooled reference was generated from the normal esophagus and stomach samples. Copy number results were plotted directly within CNVkit using the function scatter.

  Study phs003949

• National Children's Study Vanguard Study Formative Research Study (NCS)

  The National Children's Study (NCS) is a multi-year prospective epidemiological study tasked with identifying a nationally representative sample of 100,000 children and following them from pregnancy through age 21 to study environmental impacts on growth, development, and health. Determination of NCS enrollee ancestry is important for assessing the diversity of study enrollees and for examining the effect of ancestry on various health outcomes. We estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites by analyzing 29,972 markers on exome arrays, using the participants of the 1000 Genomes Project (1KG) super populations (e.g. European, East Asian) as reference populations, and compared this to self-reported ethnicity and race. Self-reported ethnicity and race agreed with predicted super population in 98.9% of individuals. NCS individuals identified as Asian by self-report had genetic ancestry of either South Asian or Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 11 (33%) matched the South Asian and Asian groups, while these groups were less represented in the other reported categories (27/609, 4.4%). Our data suggest that self-reported ethnicity and race categories have some limitations in accurately capturing this information for Hispanic and South Asian populations. Overall, our data indicate that despite the complexity of the U.S. population, individuals know their ancestral origins and that self-reported ethnicity and race is a reliable indicator of genetic ancestry.

  Study phs000662

• Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors

  Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Experimental design: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). Results: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Conclusion: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

  Study EGAS50000000315

• DNA methylation at HBV integrants and flanking host genomes

  Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either the human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis.

  Study JGAS000015