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• TONIC-Trial-cfDNA-Project

  Cell-free DNA (cfDNA) is an emerging technology to predict and monitor response to cancer treatment, including immune checkpoint blockade (ICB). However, data on cfDNA dynamics during ICB in metastatic triple negative breast cancer (mTNBC) are limited. While most applications of cfDNA involve assays that focus on mutation detection, mTNBC and multiple other cancer types are driven by copy number alterations (CNAs). We evaluate cfDNA-based copy number profile abnormality (CPA) score as a potential biomarker for monitoring ICB response in mTNBC, analyzing data from 87 patients enrolled in stage 1 and stage 2 of the TONIC-trial. We find significant concordance between cfDNA-based and tissue-based CNA profiles. Additionally, responders show a decrease in CPA scores upon ICB at week 6 (3 cycles of nivolumab). These findings underscore the potential of cfDNA-based CNA dynamics as a non-invasive biomarker for ICB early response assessment in patients with mTNBC.

  Study EGAS50000001308

• Raw RNA-seq data for clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. This dataset includes the raw RNA-seq data.

  Dataset EGAD00001006205

• ATAC-seq of metastatic prostate tumors

  This dataset includes Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data, in FASTQ format, from 70 metastatic castration-resistant prostate cancer tumor samples from the SU2C/PCF West Coast Dream Team (WCDT) project. The sequencing data is paired-end, 150 bp sequencing data from an Illumina NovaSeq 6000 machine. ATAC-seq libraries were prepared following the protocol described in Buenrostro et al. Nature Methods. 2013 (PMID: 24097267) and Corces et al. Nature Methods. 2017 (PMID: 28846090).

  Dataset EGAD00001009654

• The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma

  In classical Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with long-term-responders (LTR). In total, data from 84 samples were submitted.

  Study EGAS50000000149

• Genome-Wide Association of Native and Post Aspirin Platelet Function Phenotypes

  The goal of this study was to identify genetic variants in a genome-wide association study (GWAS) that are associated with previously obtained platelet function phenotypes measured in each individual under baseline conditions and following 2 weeks of low dose aspirin (ASA). During this study we performed a high density 1 million-SNP genome scan on subjects from GeneSTAR (representing 800 2-generational families with a family history of premature coronary artery disease, 60% white and 40% African American, N=3232). We identified genomic loci associated with quantitative platelet phenotypes prioritized for their biological interest, determined associations between genomic loci and baseline platelet phenotypes (primary phenotypes are platelet aggregation in platelet rich plasma induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine (Epi), determined associations between genomic loci and post-ASA platelet phenotypes, ie, measures of ASA "resistance" (primary phenotypes are as above, plus urinary levels of the prostaglandin metabolite, 11-dehydro-thromboxane B2 ), and compared peaks of association between genomic loci and three common baseline platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in platelet rich plasma) with associations found for these same phenotypes in the Framingham Heart Study. We also determined whether any significant genotype-phenotype associations in the 1 million SNP genome scan could be localized to any specific genes or potential genes of interest using publicly available databases and further examined whether candidate genes previously associated with a specific platelet phenotype are located in a genomic region of interest as determined from the SNP genome scan. We conducted replications of our findings, and are presently involved in larger scale meta-analysis of findings for pre-aspirin and post-aspirin associations. The study population is constituted of full siblings (SIBS) (ages 35-78 years) identified from The Johns Hopkins Sibling Study, now called GeneSTAR, the spouses of the SIBS, and their adult offspring (>21 years of age). They include 3200 individuals from approximately 300 African American and 500 white extended families. "Spouse" refers to the other parent of any SIB offspring, independent of marital status. Sibship sizes among families range from 1 to 16 (excluding index cases). On average, each SIB has 2 potentially eligible offspring. A family for this study is defined by all of the full sibships and the total numbers of offspring that come from all SIBS, rather than just the nuclear family.

  Study phs000375

• The Emirati T2T-level Pangenome: A complete Diploid Graph of 58 Genomes

  This dataset is an Emirati telomere-to-telomere (T2T) pangenome graph in GBZ format built from 116 haplotype-resolved assemblies spanning 58 individuals (28 trio-based and 30 single-sample assemblies). Assemblies were generated with long-read sequencing (PacBio HiFi and ONT ultra-long) with standard polishing, then integrated into a graph representation. The genomes show high contiguity (median ≈150 Mb) and high consensus accuracy (median QV 59). The resulting GBZ graph captures globally shared and Emirati-enriched variation, including sequence in complex regions, and serves as a population-matched reference for downstream variant discovery and annotation.

  Dataset EGAD50000001756

• IMMUcan SCCHN1 cohort

  The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients with confirmed locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who receive first-line treatment with immune checkpoint inhibitors (ICI) or ICI combined with chemotherapy. Comprehensive profiling data are integrated with longitudinally collected clinical information. Cellular profiling of the same tumor samples was performed using multiplex immunofluorescence imaging, imaging mass cytometry, and H&E staining.

  Study EGAS50000001533

• Understand Paratyphoid Disease - host responses to human challenge with S. Paratyphi A (2019-08-28)

  This project aims to evaluate the transcriptional response to disease measured in whole blood of participants who developed enteric fever after challenge and, importantly, those who were challenged but stayed well throughout the challenge period. This data will provide unique coverage of the transcriptome and will yield invaluable insight after integration with a wealth of clinical data collected during this trial. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-08-28.

  Dataset EGAD00001005298

• Rare Germline Variants in CDKN2A-Negative Children and Adolescents with Cutaneous Melanoma

  Cutaneous melanoma is a complex disease influenced by both environmental and genetic factors. Inherited susceptibility plays a significant role, involving a combination of high-, intermediate-, and low-penetrance genes. Melanoma in children and adolescents has been speculated to have a stronger genetic component due to the early onset. This study investigates germline variants in early-onset melanoma through exome sequencing of 154 patients in Australia diagnosed with cutaneous melanoma before the age of 20.

  Study EGAS50000001311

• Mutations in SPINK2 induce azoospermia

  Azoospermia, characterized by the absence of spermatozoa in the ejaculate is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit towards the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

  Study EGAS00001002450