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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Zhou, Q; Perakis, SO; Ulz, P; Mohan, S; Riedl, JM; Talakic, E; Lax, S; Tötsch, M; Hoefler, G; Bauernhofer, T; Pichler, M; Gerger, A; Geigl, JB; Heitzer, E; Speicher, MR.
Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer.
Genome Med. 2020; 12(1):20 Doi: 10.1186/s13073-020-0719-6 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Führende Autor*innen der Med Uni Graz
Hasenleithner Samantha
Speicher Michael
Zhou Qing
Co-Autor*innen der Med Uni Graz
Bauernhofer Thomas
Geigl Jochen Bernd
Gerger Armin
Heitzer Ellen
Höfler Gerald
Mohan Sumitra
Pichler Martin
Riedl Jakob
Talakic Emina
Tötsch Martin
Ulz Peter

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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.
Find related publications in this database (using NLM MeSH Indexing)
Adult - administration & dosage
Aged - administration & dosage
Aged, 80 and over - administration & dosage
Antineoplastic Agents, Immunological - therapeutic use
Bevacizumab - therapeutic use
Cell Proliferation - administration & dosage
Cell-Free Nucleic Acids - genetics
Chromosomes, Human, Pair 13 - genetics
Colorectal Neoplasms - drug therapy, genetics, pathology
DNA-Directed RNA Polymerases - genetics, metabolism
Drug Resistance, Neoplasm - administration & dosage
Female - administration & dosage
Gene Amplification - administration & dosage
HT29 Cells - administration & dosage
Humans - administration & dosage
Male - administration & dosage
Middle Aged - administration & dosage
Neoplasm Metastasis - administration & dosage
Up-Regulation - administration & dosage
Vascular Endothelial Growth Factor A - genetics, metabolism

Find related publications in this database (Keywords)
Cell-free DNA
Whole-genome sequencing
Therapy resistance
Precision medicine
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