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@ARTICLE{Fischer:302322,
      author       = {T. Fischer$^*$ and K. Maass$^*$ and P. Puranachot$^*$ and
                      M. Mieskolainen and M. Sill$^*$ and P. Schad$^*$ and S.
                      Volz$^*$ and F. Rosing$^*$ and T. Wedig$^*$ and N.
                      Schwarz$^*$ and A. Finster$^*$ and F. Iser$^*$ and J.
                      Meyer$^*$ and F. Sahm$^*$ and O. Lohi and A. E. Damaty and
                      B. Brors$^*$ and H. Haapasalo and S. Pfister$^*$ and J.
                      Haapasalo and K. Pajtler$^*$ and K. Nordfors},
      title        = {{U}ltra-low-input cell-free {DNA} sequencing for tumor
                      detection and characterization in a real-world pediatric
                      brain tumor cohort.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {13},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-01317},
      pages        = {134},
      year         = {2025},
      note         = {#EA:B062#LA:B062#},
      abstract     = {Molecular profiling of pediatric central nervous system
                      (CNS) tumors has important clinical utility for guiding
                      diagnostic and therapeutic strategies. Cell-free DNA (cfDNA)
                      from liquid biopsies has been used for minimally invasive
                      tumor profiling and longitudinal disease assessment in adult
                      oncology and pediatric hematology. However, in pediatric
                      neuro-oncology, low cfDNA yields pose a major barrier to
                      translating these assays from bench to bedside. Here, we
                      implemented a low-coverage whole genome sequencing (lcWGS)
                      assay for picogram-level cfDNA inputs and applied it to
                      liquid biopsies from a sizeable, population-based,
                      cross-entity pediatric CNS tumor cohort (n = 56 patients).
                      Applying this protocol, cfDNA whole genome profiles were
                      successfully acquired from all liquid biopsy samples (n =
                      61/61 serum, n = 56/56 CSF, $100\%).$ Based on copy number
                      variations (CNVs), circulating-tumor DNA (ctDNA) was
                      detected in 2/61 serum $(3\%)$ and in 25/56 CSF $(45\%)$
                      samples across various brain tumor entities. The integration
                      of cfDNA results with clinical data demonstrated the utility
                      of CSF lcWGS as a biomarker assay at diagnosis to
                      distinguish cancerous from non-cancerous pineal region
                      lesions (n = 6 patients). Additionally, serial CSF
                      assessment in n = 9 patients (n = 29 CSF samples) enabled
                      minimally invasive disease monitoring, with the added value
                      of molecular profile availability in n = 4/6 $(67\%)$
                      patients at relapse. Proof-of-concept data show the
                      feasibility of serial CSF lcWGS to reveal tumor evolution,
                      tumor heterogeneity and potential therapeutic
                      vulnerabilities in a case of medulloblastoma and germ cell
                      tumor. Our study underscores the clinical utility of a
                      robust lcWGS-based liquid biopsy assay optimized for
                      low-input samples. We identify use-cases for implementing
                      liquid biopsies in the clinical management of pediatric CNS
                      tumor patients and provide a strong rationale for
                      integration into future trials.},
      keywords     = {Humans / Child / Male / Brain Neoplasms: genetics / Brain
                      Neoplasms: diagnosis / Brain Neoplasms: cerebrospinal fluid
                      / Brain Neoplasms: blood / Female / Child, Preschool /
                      Adolescent / Cohort Studies / Whole Genome Sequencing:
                      methods / Biomarkers, Tumor: cerebrospinal fluid /
                      Biomarkers, Tumor: genetics / Biomarkers, Tumor: blood /
                      Liquid Biopsy / Circulating Tumor DNA: cerebrospinal fluid /
                      Circulating Tumor DNA: genetics / Circulating Tumor DNA:
                      blood / Cell-Free Nucleic Acids / Infant / DNA Copy Number
                      Variations / Cell-free DNA (Other) / Cerebrospinal fluid
                      liquid biopsies (Other) / Circulating-tumor DNA (Other) /
                      Copy number variation profiling (Other) / Longitudinal
                      molecular biomarkers (Other) / Low-coverage whole genome
                      sequencing (Other) / Low-input samples (Other) /
                      Minimally-invasive disease monitoring (Other) / Pediatric
                      neuro-oncology (Other) / Tumor evolution (Other) /
                      Biomarkers, Tumor (NLM Chemicals) / Circulating Tumor DNA
                      (NLM Chemicals) / Cell-Free Nucleic Acids (NLM Chemicals)},
      cin          = {B062 / HD01 / B330 / B320 / B300},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B330-20160331 / I:(DE-He78)B320-20160331 /
                      I:(DE-He78)B300-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40579709},
      doi          = {10.1186/s40478-025-02024-w},
      url          = {https://inrepo02.dkfz.de/record/302322},
}