@article{8674319,
  abstract     = {{Background: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. Methods: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. Results: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (>= 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with >= 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. Conclusions: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.}},
  articleno    = {{85}},
  author       = {{Mayrhofer, Markus and De Laere, Bram and Whitington, Tom and Van Oyen, Peter and Ghysel, Christophe and Ampe, Jozef and Ost, Piet and Demey, Wim and Hoekx, Lucien and Schrijvers, Dirk and Brouwers, Barbara and Lybaert, Willem and Everaert, Els and De Maeseneer, Daan and Strijbos, Michiel and Bols, Alain and Fransis, Karen and Oeyen, Steffi and van Dam, Pieter-Jan and Van den Eynden, Gert and Rutten, Annemie and Aly, Markus and Nordstrom, Tobias and Van Laere, Steven and Rantalainen, Mattias and Rajan, Prabhakar and Egevad, Lars and Ullen, Anders and Yachnin, Jeffrey and Dirix, Luc and Gronberg, Henrik and Lindberg, Johan}},
  issn         = {{1756-994X}},
  journal      = {{GENOME MEDICINE}},
  keywords     = {{CIRCULATING TUMOR-CELLS,MESSENGER-RNA DETECTION,BONE-MARROW BIOPSY,CLINICAL-SIGNIFICANCE,2ND-LINE ABIRATERONE,TISSUE ACQUISITION,INCREASED SURVIVAL,OPEN-LABEL,ENZALUTAMIDE,MUTATIONS,Circulating tumor DNA,Metastatic prostate cancer,Microsatellite,instability,Structural rearrangement,Clonal hematopoiesis}},
  language     = {{eng}},
  pages        = {{13}},
  title        = {{Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis}},
  url          = {{http://doi.org/10.1186/s13073-018-0595-5}},
  volume       = {{10}},
  year         = {{2018}},
}

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