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• Molecular Signatures of DCIS to Invasive Progression for Basal-Like Breast Cancers: An Integrated Mouse Model and Human Tumor Study

  We studied the genomic signatures of progression in breast ductal carcinoma in situ (DCIS) as it progresses towards triple negative invasive breast cancer (TNBC). Single cell RNA sequencing (scRNAseq) was performed on the C3Tag genetically engineered mouse model that forms human breast-like DCIS and TNBC. Bulk RNA sequencing was performed on RNA harvested from archival formalin-fixed, paraffin embedded (FFPE) pairs comprising of estrogen receptor (ER) positive (ER+) and negative (ER-) subsets of DCIS. 

  Study phs002443

• Human Skin Cancer Atlas, Medical University of Vienna Data Access Policy

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Dac EGAC50000000154

• Identification of therapeutic target molecules for prostate cancer by using next generation sequencer

  Comprehensive transcriptional characterization of cancer tissues can reveal important molecular signatures associated with the disease progression. Long non-coding RNA (LncRNA) has a diversity of functions such as transcription, epigenetic and gene regulation in cancer cells including prostate cancer cells. Here, we performed directional RNA-sequence (RNA-seq) on clinical samples obtained from prostate cancer (PC) and lethal castration-resistant PC (CRPC) patients to identify novel molecular signatures including protein coding genes and non-coding RNAs induced in CRPC tissues.

  Study JGAS000198

• Targeted panel data for newly diagnosed myeloma patients.

  Genomic abnormalities in MM are common and can affect a patients outcome. Here we have performed targeted sequencing on xx patient tumor samples and matched control DNA. The targeted panel consists of ~160 genes and copy number regions, as well as key regions of chromosomal translocation including IGH, IGK, IGL and MYC. Using mutation, copy number, and translocation information we have been able to identify abnormalities that affect prognosis including bi-allelic inactivation of TP53 and rearrangements involving MYC.

  Study EGAS00001002859

• Illumina RNA sequencing for HLA expression qauntification

  In this study, we quantified mRNA expression levels of HLA class I and II genes from peripheral blood samples of 50 healthy individuals. The gene- and allele-specific mRNA expression was assessed using unique molecular identifiers, which enabled PCR bias removal and calculation of the number of original mRNA transcripts. We identified differences in mRNA expression between different HLA genes and alleles. Our results suggest that HLA alleles are differentially expressed and these differences in expression levels are quantifiable using RNA sequencing technology.

  Study EGAS00001004931

• Transcriptomic predictors of survival for palbociclib + endocrine therapy vs. capecitabine in aromatase inhibitor-resistant breast cancer from GEICAM/2013-02 PEARL

  We examined transcriptomic tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET vs. capecitabine in aromatase inhibitor-resistant HR+/HER2- MBC. PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine, and lower B-cell-associated gene expression predicted longer OS with palbociclib + ET vs. capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6 inhibitors.

  Study EGAS00001008177

• Guardians of the genome: protecting DNA from endogenous sources of damage

  Mutational signatures are imprints of cell-intrinsic and extrinsic pathophysiological processes that have occurred through tumorigenesis. Experimental efforts to explore signature etiologies have produced a compendium of signatures of exogenous mutagens previously. Here, we unearth major sources of endogenous DNA damage and the genes that are critical to mitigating this innate stream of DNA damage under normal, physiological circumstances. We performed whole genome sequencing of 173 subclones of CRISPR-Cas9 knockouts of 43 genes in a human induced pluripotent stem cell system, in the absence of any added DNA damage. We reveal substitution and indel signatures that arise from those genes which are essential guardians of the genome. By detailed dissection and comparisons to cancer-derived signatures, we demonstrate interminable sources of constitutive DNA damage, and some mechanistic knowledge into how guardian genes preserve the genome. Based on these experimental insights, we develop and benchmark a tool for clinical classification of tumor samples.

  Dataset EGAD00001006055

• Methylation and nucleosome occupancy studies on cell-free DNA using enzymatic cytosine conversion

  Raw sequencing data (PE, fastq.gz) from NovaSeq 6000 sequencing runs of: 1. Blood-derived cell-free DNA from six healthy controls, enzymatic cytosine conversion (between 1 and 3 replicates each) 2. Urine-derived cell-free DNA from three healthy controls, enzymatic cytosine conversion (between 1 and 3 replicates each) 3. Blood-derived cell-free DNA from six patients with acute or chronic kidney disease with/without other relevant organ dysfunction, enzymatic cytosine conversion (between 1 and 3 replicates each) 4. Urine-derived cell-free DNA from three patients with acute kidney disease, enzymatic cytosine conversion (between 1 and 3 replicates each) 5. Blood-derived cell-free DNA from three healthy controls, bisulfite cytosine conversion (single datasets) 6. Conventional whole-genome sequencing on genomic DNA of two healthy kidney donors for two of the studied patients (single datasets).

  Dataset EGAD00001006072

• Combinatorial CRISPR screen identifies fitness effects of paralogues FAM50A and FAM50B

  Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1,191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. This dataset includes CRISPR screening of cancer cell lines, RNA sequencing studies of cancer cell lines and also data from the sequencing of tumour xenografts collected from mice.

  Dataset EGAD00001006649

• Spatial multi-omic map of human myocardial infarction

  We applied an integrative single-cell genomics strategy with single nucleus RNA sequencing (snRNA-seq) and single nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) together with spatial transcriptomics from the same tissue mapping human cardiac cells in homeostasis and after myocardial infarction (MI) at unprecedented spatial and molecular resolution. We profiled in total 31 samples from 23 patients including four non-transplanted donor hearts as controls and samples from tissues with necrotic tissue areas (ischemic zone, IZ), border zone (BZ), and the non-affected left ventricular myocardium (remote zone, RZ) of patients with acute MI.

  Dataset EGAD00001008952