Roland F. Schwarz's research while affiliated with University of Cologne and other places

Publications (94)

Preprint
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Neuroblastoma is characterised by extensive inter- and intra-tumour genetic heterogeneity and varying clinical outcomes. One possible driver for this heterogeneity are extrachromosomal DNAs (ecDNA), which segregate independently to the daughter cells during cell division and can lead to rapid amplification of oncogenes. While ecDNA-mediated oncogen...
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Mutations in simple sequence repeat loci underlie many inherited disorders in humans, and are increasingly recognized as important determinants of natural phenotypic variation. In eukaryotes, mutations in these sequences are primarily repaired by the MutSβ mismatch repair complex. To better understand the role of this complex in mismatch repair and...
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Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-ce...
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Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient’s disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplot...
Preprint
Full-text available
Mutations in simple sequence repeat loci underlie many inherited disorders in humans, and are increasingly recognized as important determinants of natural phenotypic variation. In eukaryotes, mutations in these sequences are primarily repaired by the MutSβ mismatch repair complex. To better understand the role of this complex in mismatch repair and...
Preprint
Full-text available
Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either TERT activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only presen...
Article
Extrachromosomal DNA circularization is a common event in cancer cells and frequently serves as a vehicle for cancer oncogene amplification. Random segregation of oncogene-containing extrachromosomal circular DNA promotes rapid intercellular heterogeneity, conferring tumors the ability to rapidly evolve and escape therapy. Smaller, copy-number neut...
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Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although certain complex genomic alterations, such as extrachromosomal DNA amplifications (ecDNA), have been recurrently detected in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography of com...
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Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the...
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Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutation...
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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non...
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Motivation: Genome Architecture Mapping (GAM) was recently introduced as a digestion- and ligation-free method to detect chromatin conformation. Orthogonal to existing approaches based on chromatin conformation capture (3C), GAM's ability to capture both inter- and intra-chromosomal contacts from low amounts of input data makes it particularly wel...
Preprint
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Chromosomal instability (CIN) and somatic copy number alterations (SCNA) play a key role in the evolutionary process that shapes cancer genomes. SCNAs comprise many classes of clinically relevant events, such as localised amplifications, gains, losses, loss-of-heterozygosity (LOH) events, and recently discovered parallel evolutionary events reveale...
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Bei der bereits veröffentlichten Originalversion des Artikels ist ein Fehler in der Abbildung 2B entstanden: bei der Kennzeichnung der Herkunft des Chromosom 4 wurde die falsche Patienten-ID angeben, korrekt ist die ID „CRUK0009“ Anbei finden Sie die korrigierte Version. Wir entschuldigen uns für den Fehler und für alle dadurch eventuell entstanden...
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Objective: The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize t...
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Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to...
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Intra-tumour heterogeneity is a key characteristic of tumours and poses significant clinical challenges. Despite extensive research, the evolutionary processes shaping cancer genomes are not yet fully understood. We here discuss two conflicting theories about the evolution of solid tumours: the Big Bang model and the classical model of continuous e...
Preprint
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The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG...
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Transcript alterations often result from somatic changes in cancer genomes¹. Various forms of RNA alterations have been described in cancer, including overexpression², altered splicing³ and gene fusions⁴; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relativ...
Preprint
Full-text available
Motivation Genome Architecture Mapping (GAM) was recently introduced as a digestion- and ligation-free method to detect chromatin conformation. Orthogonal to existing approaches based on chromatin conformation capture (3C), GAM’s ability to capture both inter- and intra-chromosomal contacts from low amounts of input data makes it particularly well...
Article
Full-text available
Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma,...
Preprint
Full-text available
Objective The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the...
Data
Table S3. TRACERx Renal Cohort: Multiregional Ki67 Immunohistochemistry Staining Analysis, Related to Figure 4
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Table S1. TRACERx Renal Cohort: Clinical Characteristics, Evolutionary Subtypes, Progression Patterns, and Survival Outcomes, Related to Figure 1
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Data S2. Mutation Heatmap and Driver Trees for a Subset of TRACERx Renal Cohort, Related to Figures 1 and 2 Mutation heatmap and driver trees, for individual cases as referenced in the Results section.
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Table S4. TCGA KIRC Cohort: Multivariate Survival Analysis and Processing Notes, Related to Figure 7 and STAR Methods
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Table S5. Comparison of Clone Numbers Detectable from Driver Panel and Whole Exome Sequencing in the Same Cases, Related to STAR Methods The left panel shows the raw clone numbers for each case, per sequencing data type. The right panel shows the correlation of number of tumor clones identified using Renal Driver panel (x axis) and whole exome seq...
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Table S2. TRACERx Renal Driver Panels and Detected Somatic Alternations, Related to Figure 1 and STAR Methods
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Data S3. Copy Neutral Allelic Imbalance, MSAI, and SCNA Profiles for Bilateral and Multifocal Tumors, Related to Figures 1 and 3 and STAR Methods Page 1 shows copy neutral allelic imbalance data. Pages 2-17 shows case level MSAI results. Page 18 shows a summary of MSAI results. Pages 19-20 shows MSAI validation results. Page 21 shows SCNA profiles...
Data
Data S4. TRACERx Renal Cohort: Correlation of Driver Events Versus Clinical Variables and Tumor Size versus Number of Clones, Related to Figure 1 and STAR Methods Shown on page 1 are boxplots illustrating comparison of number of variants, ITH score or number of clones classified variously by Tumour Size (in cm), Overall Stage, Grade and Tumour Nec...
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The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known pr...
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Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic res...
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As sequencing efforts continue to reveal the extent of the intratumor heterogeneity (ITH) present in human cancers, the importance of evolutionary studies attempting to trace its etiology has increased. Sequencing multiple samples or tumor regions from the same patient has become affordable and is an effective way of tracing these evolutionary path...
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Whole-exome sequencing studies have transformed our understanding of recurrent somatic mutations that contribute to cancer pathogenesis; however, these studies limit our ability to identify cancer-associated mutations to those that cause protein-coding changes. To more comprehensively catalogue cancer-associated gene alterations, we have extensivel...
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Introduction: We present a novel method to identify cancer driver genes that jointly examines any number of diverse transcriptomic alterations with the goal to uncover highly recurrent and heterogeneous patterns in 1190 samples across 26 cancer types as part of the PanCancer Analysis of Whole Genomes (PCAWG) of the International Cancer Genome Conso...
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Background Among patients with non–small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary process...
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The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. He...
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Sequence Logos and its variants are the most commonly used method for visualization of multiple sequence alignments (MSAs) and sequence motifs. They provide consensus-based summaries of the sequences in the alignment. Consequently, individual sequences cannot be identified in the visualization and covariant sites are not easily discernible. We rece...
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Author Summary Technology for recording neural activity is advancing rapidly and whole-brain imaging with single neuron resolution has already been demonstrated for smaller animals. To interpret such complex neural recordings, we need comprehensive characterizations of behaviour, which is the principal output of the brain. Animal tracking can incre...
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Locomotion is driven by shape changes coordinated by the nervous system through time; thus, enumerating an animal's complete repertoire of shape transitions would provide a basis for a comprehensive understanding of locomotor behaviour. Here we introduce a discrete representation of behaviour in the nematode C. elegans. At each point in time, the w...
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The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was...
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Cancer is a somatic evolutionary process characterized by the accumulation of mutations, which contribute to tumor growth, clinical progression, immune escape, and drug resistance development. Evolutionary theory can be used to analyze the dynamics of tumor cell populations and to make inference about the evolutionary history of a tumor from molecu...
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Background We introduce Sequence Bundles--a novel data visualisation method for representing multiple sequence alignments (MSAs). We identify and address key limitations of the existing bioinformatics data visualisation methods (i.e. the Sequence Logo) by enabling Sequence Bundles to give salient visual expression to sequence motifs and other data...
Chapter
This chapter on mechanisms of genome plasticity in Neisseria meningitidis initially gives a short overview over the genetic variability at the population level and some peculiarities of meningococcal genome organization as revealed by genome sequencing projects. Later, the focus is on genetic mechanisms and genomic features that are paramount for t...
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Intra-tumour genetic heterogeneity is the result of ongoing evolutionary change within each cancer. The expansion of genetically distinct sub-clonal populations may explain the emergence of drug resistance, and if so, would have prognostic and predictive utility. However, methods for objectively quantifying tumour heterogeneity have been missing an...
Article
Solid tumors are heterogeneous tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Furthermore, tissue architecture is generally not reflected in molecular assays, rendering this rich information underused. To address these challenges, we developed a computational approach base...
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It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA-based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative f...
Article
Comparing proteomics and metabolomics allows insights into Staphylococcus aureus physiological growth. We update genome and proteome information and deliver strain-specific metabolic models for three S. aureus strains (COL, N315, and Newman). We find a number of differences in metabolism and enzymes. Growth experiments (glucose or combined with oxy...
Data
Distribution of surface and virulence-associated proteins. Only surface and virulence-associated proteins are shown that are variably present among the 29 meningococcal strains compared. The respective genes were taken from recent compilations given in refs. [14], [84]. (TIF)
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Genetic structure of the sample population based on MLST. Dot graph representation based on a majority rule consensus tree of the seven housekeeping gene fragments form the meningococcal core genome used for MLST calculated with ClonalFrame. Based on the sequence in housekeeping genes genomic groups as defined by mCGH are torn apart such as GG-II (...
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Genes specifically present or absent in only one genome group. (DOC)
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Core genes of the sample population with significant evidence for recombination in the ΦW statistic. (DOC)
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Genes differently distributed between pairs of strains from the same ST. (DOC)
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Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing...
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Genes specific for strains from hyperinvasive lineages within GG-VI. (DOC)
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Overview of the important population genetic data of the sample population. (DOC)
Article
Transcriptional regulators play an important role for the survival of Neisseria meningitidis within its human host. We have recently shown that FarR acts as transcriptional repressor of the adhesin nadA in N. meningitidis. Here, we examined the FarR regulon by microarray analyses, qRT-PCR, and electrophoretic mobility shift assays, revealing that F...
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Phylogenetic tree reconstruction is traditionally based on multiple sequence alignments (MSAs) and heavily depends on the validity of this information bottleneck. With increasing sequence divergence, the quality of MSAs decays quickly. Alignment-free methods, on the other hand, are based on abstract string comparisons and avoid potential alignment...
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The internal transcribed spacer 2 (ITS2) is a widely used phylogenetic marker. In the past, it has mainly been used for species level classifications. Nowadays, a wider applicability becomes apparent. Here, the conserved structure of the RNA molecule plays a vital role. We have developed the ITS2 Database (http://its2.bioapps.biozentrum.uni-wuerzbu...