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• Longitudinal analysis of treatment induced genomic alterations in gliomas

  Here, we report the longitudinal whole exome sequencing analysis of a patient with a primary GBM and two recurrences, demonstrating the heterogeneity caused by the therapy induced molecular changes and their implications for clinical decision-making. This analysis revealed the impact of temporal evolution for tumors under the pressure of treatment. We presented that while targeted treatments eliminated some sensitive clones, there were clones that were enriched leading to resistance. This study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of therapy induced molecular changes to improve the outcomes of precision therapies.

  Study EGAS00001002168

• cfRRBS methylation profiling of cfDNA from cerebrospinal fluid from pediatric CNS tumor patients

  In this study, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the cell-free DNA in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected 20 cerebrospinal fluid samples of pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. For 11 patients in this study we collected matched tumor DNA. This cohort contains fastQ files of cfRRBS data of these samples.

  Dataset EGAD50000000554

• The evolution of hematopoietic cells under cancer therapy

  Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs showed the mutational footprint of these drugs, indicating that non-malignant blood cells received chemotherapy mutations. No trace of 5-fluorouracil (5FU) mutational signature was found in AML secondary to exposure to 5FU, suggesting that cells establishing the AML were quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determined that secondary AMLs began their clonal expansion after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with a clonal expansion that predates the exposure to the cytotoxic agent.

  Study EGAS00001005234

• The Effects of Long-Term Heavy Metal Exposure on Transcriptome Landscape in Human Peripheral Blood Cells

  The present study investigates the impact of long-term residence in a mining area on transcriptome changes induced by heavy metal exposure in human peripheral blood mononuclear cells (PBMCs) from 65 healthy subjects selected from the general population. This study includes the same participants which were recruited in our previous investigation on heavy metal long-term environmental exposure-related gene-specific methylation changes (phs003392.v1.p1). We performed a differential expression analysis to compare the mRNA transcriptome of 31 residents from the mining region (MRR) - individuals living in the Kapan mining area with reported environmental exposures to heavy metals - with that of 34 residents from non-mining regions (NMR) - individuals residing at a considerable distance from mining locations. We also evaluated the potential association of gene expression profiles with the blood metallome, including levels of Ca, Mg, Co, Fe, Mn, Cu, Mo, Se, Zn, As, Sb, Tl, Be, V, Ni. Poly-A selected strand-specific mRNA library was prepared with Illumina Stranded mRNA Prep kit. The sequencing was performed on the Illumina NovaSeq-6000 platform with 38.5 million single-end 100 bp reads on average generated per sample. Quality checking of the sequencing data was performed using Illumina Basespace reports and the program FastQC (V0.10.1). Reads were aligned against the Human Genome Hg38 using STAR (version 2.7.1a). According to our findings, long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. Pathway analysis revealed upregulation of immune response related pathways, and downregulation of translation and ribosome biogenesis in the PBMCs of the MRR. Pathways related to metal ion transmembrane transport, epigenetic modifications (histone deacetylases (HDACs) and DNA methylation) were upregulated in males, while in females mostly transcripts involved in inflammation and cytokine mediated signaling were upregulated. Additionally, among the dysregulated pathways, the TNF-α signaling via NF-κB showed opposite changes in females and males.

  Study phs003657

• Genetic Analysis of Tuberous Sclerosis Complex (TSC) Hypomelanotic Macules

  In this study we searched for mutations in the TSC1 and TSC2 genes in cultured melanocytes from individuals with the genetic disease Tuberous Sclerosis Complex.

  Study phs001236

• Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia

  Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41).  Complex karyotype by cytogenetics emerges as a heterogeneous group, underlied by distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.

  Dataset EGAD00001009304

• Single-Cell Transcriptomics of Adult Recurrent Respiratory Papillomatosis

  These single-cell sequencing data were generated from diseased respiratory tract papilloma tissue caused by chronic infection with HPV 6 or 11. Patients from which this tissue was derived participated in a phase I clinical trial using a novel therapeutic vaccine, but these samples were acquired before this experimental treatment. The aim of performing this single-cell sequencing study was to characterize the papilloma cells and other cells in the papilloma microenvironment with single-cell analyses using the 10X Genomics platform. The single-cell gene expression raw data files for each sample will be available in this submission.

  Study phs003349

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• cfDNA Methylomes for HCC Detection and Postoperative Monitoring

  To overcome the limitations of current ctDNA-based HCC detection, specifically mutational profiling, we propose quantifying cfDNA methylation levels using cfMeDIP-seq and evaluating its capacity for HCC detection and post-surgery recurrence monitoring. This approach aims to reveal the clonal dynamics of HCC during surgery and upon relapse. Our preliminary data and analyzed results demonstrate that tumor-agnostic cfDNA methylomes can accurately detect HCC and predict recurrence after liver resection or transplantation. This method could have significant implications for the diagnosis, treatment, and monitoring of HCC.

  Study EGAS50000000450

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - WGS

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011645