Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer
AffiliationInstitute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz,
MetadataShow full item record
AbstractBACKGROUND: 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.
CitationZhou Q, Perakis SO, Ulz P, Mohan S, Riedl JM, Talakic E, et al. Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer. Genome Med. 2020;12:20.
- FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA.
- Authors: Wang S, Xiao Z, Hong Z, Jiao H, Zhu S, Zhao Y, Bi J, Qiu J, Zhang D, Yan J, Zhang L, Huang C, Li T, Liang L, Liao W, Ye Y, Ding Y
- Issue date: 2018 Dec 28
- Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.
- Authors: Burgermeister E, Battaglin F, Eladly F, Wu W, Herweck F, Schulte N, Betge J, Härtel N, Kather JN, Weis CA, Gaiser T, Marx A, Weiss C, Hofheinz R, Miller IS, Loupakis F, Lenz HJ, Byrne AT, Ebert MP
- Issue date: 2019 Jul
- <i>VEGF-A</i> and <i>ICAM-1</i> Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer.
- Authors: Papachristos A, Kemos P, Katsila T, Panoilia E, Patrinos GP, Kalofonos H, Sivolapenko GB
- Issue date: 2019 Nov 18
- Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer.
- Authors: Zuurbier L, Rahman A, Cordes M, Scheick J, Wong TJ, Rustenburg F, Joseph JC, Dynoodt P, Casey R, Drillenburg P, Gerhards M, Barat A, Klinger R, Fender B, O'Connor DP, Betge J, Ebert MP, Gaiser T, Prehn JHM, Griffioen AW, van Grieken NCT, Ylstra B, Byrne AT, van der Flier LG, Gallagher WM, Postel R
- Issue date: 2017 Jun 27
- Decreased peritherapeutic VEGF expression could be a predictor of responsiveness to first-line FOLFIRI plus bevacizumab in mCRC patients.
- Authors: Tsai HL, Lin CH, Huang CW, Yang IP, Yeh YS, Hsu WH, Wu JY, Kuo CH, Tseng FY, Wang JY
- Issue date: 2015