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      Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

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          Abstract

          Background

          Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance.

          Methods

          Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort ( n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database ( n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset.

          Results

          We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance.

          Conclusions

          Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

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          Most cited references 41

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          Patterns of somatic mutation in human cancer genomes.

          Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
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            Determinants of nucleosome organization in primary human cells

            Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodeling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome 1 . Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions 2–4 . To identify major determinants of nucleosome organization in the human genome, we utilized deep sequencing to map nucleosome positions in three primary human cell types and in vitro. A majority of the genome exhibited substantial flexibility of nucleosome positions while a small fraction showed reproducibly positioned nucleosomes. Certain sites that position in vitro can anchor the formation of nucleosomal arrays that have cell type-specific spacing in vivo. Our results unveil an interplay of sequence-based nucleosome preferences and non-nucleosomal factors in determining nucleosome organization within mammalian cells.
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              Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.

               J Tie,  I Kinde,  Y. WANG (2015)
              Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy.
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                Author and article information

                Contributors
                michael.speicher@medunigraz.at
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                22 February 2020
                22 February 2020
                2020
                : 12
                Affiliations
                [1 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Institute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, , Medical University of Graz, ; Graz, Austria
                [2 ]Present address: Freenome, South San Francisco, CA USA
                [3 ]GRID grid.5379.8, ISNI 0000000121662407, Present address: Cancer Research UK-Manchester Institute, ; Manchester, UK
                [4 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Department of Internal Medicine, Division of Oncology, , Medical University of Graz, ; Graz, Austria
                [5 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Division of General Radiology, , Medical University of Graz, ; Graz, Austria
                [6 ]Department of Pathology, General Hospital Graz II, Graz, Austria
                [7 ]GRID grid.9970.7, ISNI 0000 0001 1941 5140, Johannes Kepler University Linz, ; Linz, Austria
                [8 ]Institute of Pathology, General Hospital Hochsteiermark, Leoben, Austria
                [9 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, , Medical University of Graz, ; Graz, Austria
                [10 ]GRID grid.452216.6, BioTechMed-Graz, ; Graz, Austria
                [11 ]Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, Graz, Austria
                Article
                719
                10.1186/s13073-020-0719-6
                7036260
                32087735
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100010767, Innovative Medicines Initiative;
                Award ID: 115749-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100006012, Christian Doppler Forschungsgesellschaft;
                Award ID: Liquid Biopsy for Early Cancer Detection
                Award Recipient :
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                © The Author(s) 2020

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