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@ARTICLE{Janke:299582,
      author       = {F. Janke$^*$ and M. Gasser$^*$ and A. K. Angeles$^*$ and A.
                      L. Riediger$^*$ and M. Görtz$^*$ and L. Appenheimer$^*$ and
                      A. K. Laut$^*$ and S. Ogrodnik$^*$ and S. Gerhardt$^*$ and
                      A. Stenzinger$^*$ and M. A. Schneider and M. Thomas and P.
                      Christopoulos and H. Sültmann$^*$},
      title        = {{L}ow-coverage whole genome sequencing of cell-free {DNA}
                      to predict and track immunotherapy response in advanced
                      non-small cell lung cancer.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {44},
      number       = {1},
      issn         = {0392-9078},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2025-00523},
      pages        = {87},
      year         = {2025},
      note         = {#EA:B063#LA:B063#},
      abstract     = {Outcomes under anti-PD-(L)1 therapy have been variable in
                      advanced non-small cell lung cancer (NSCLC) without reliable
                      predictive biomarkers so far. Targeted next-generation
                      sequencing (NGS) of circulating tumor DNA (ctDNA) has
                      demonstrated potential clinical utility to support clinical
                      decisions, but requires prior tumor genetic profiling for
                      proper interpretation, and wide adoption remains limited due
                      to high costs.Tumor-agnostic low-coverage ctDNA whole genome
                      sequencing (lcWGS) was used to longitudinally track
                      genome-wide copy number variations (CNVs) and fragmentation
                      features in advanced NSCLC patients (n = 118 samples from 49
                      patients) and healthy controls (n = 57). Tumor PD-L1
                      expression was available for comparison.Fragmentation
                      features and CNVs were complementary indicators, whose
                      combination significantly increased ctDNA detection compared
                      to single-marker assessments (+ $20.3\%$ compared to CNV
                      analysis alone). Baseline fragment length alterations, but
                      not CNVs, were significantly associated with subsequent
                      progression-free survival (PFS; hazard ratio [HR] = 4.10, p
                      = 6.58e-05) and could improve PFS predictions based on tumor
                      PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs
                      or aberrant fragmentation of ctDNA under ongoing therapy
                      could stratify patients according to the subsequent response
                      duration (median 5.8 vs. 47.0 months, p = 1.13e-06). The
                      integrative analysis of ctDNA fragment characteristics at
                      baseline, tumor PD-L1 expression, and residual ctDNA under
                      ongoing treatment constituted the strongest independent
                      predictor of PFS (p = 6.25e-05) and overall survival (p =
                      1.3e-03) in multivariable analyses along with other
                      clinicopathologic variables.This study demonstrates the
                      feasibility and potential clinical utility of lcWGS for the
                      tumor-agnostic stratification and monitoring of advanced
                      NSCLC under PD-(L)1 blockade based on CNV and fragmentomic
                      profiling.},
      keywords     = {Humans / Carcinoma, Non-Small-Cell Lung: genetics /
                      Carcinoma, Non-Small-Cell Lung: drug therapy / Carcinoma,
                      Non-Small-Cell Lung: pathology / Carcinoma, Non-Small-Cell
                      Lung: immunology / Lung Neoplasms: genetics / Lung
                      Neoplasms: drug therapy / Lung Neoplasms: pathology / Lung
                      Neoplasms: immunology / Male / Female / Middle Aged / Aged /
                      Whole Genome Sequencing: methods / Immunotherapy: methods /
                      Cell-Free Nucleic Acids: genetics / Circulating Tumor DNA:
                      genetics / Circulating Tumor DNA: blood / DNA Copy Number
                      Variations / Biomarkers, Tumor: genetics / Adult / Aged, 80
                      and over / CfDNA fragmentation (Other) / Copy number
                      variations (Other) / Immunotherapy (Other) / Liquid biopsy
                      (Other) / Low-coverage whole genome sequencing (Other) /
                      Non-small cell lung cancer (Other) / Response prediction
                      (Other) / Cell-Free Nucleic Acids (NLM Chemicals) /
                      Circulating Tumor DNA (NLM Chemicals) / Biomarkers, Tumor
                      (NLM Chemicals)},
      cin          = {B063 / E250 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B063-20160331 / I:(DE-He78)E250-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40055810},
      pmc          = {pmc:PMC11889826},
      doi          = {10.1186/s13046-025-03348-0},
      url          = {https://inrepo02.dkfz.de/record/299582},
}