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@ARTICLE{Pretzsch:298930,
      author       = {E. Pretzsch$^*$ and C. A. Peschel and M. Rokavec and L.
                      Torlot and P. Li and H. Hermeking$^*$ and J. Werner$^*$ and
                      F. Klauschen$^*$ and J. Neumann$^*$ and A. Jung$^*$ and J.
                      Kumbrink$^*$},
      title        = {{F}ive-gene expression signature associated with acquired
                      {FOLFIRI} resistance and survival in metastatic colorectal
                      cancer.},
      journal      = {Laboratory investigation},
      volume       = {105},
      number       = {5},
      issn         = {0023-6837},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-00364},
      pages        = {104107},
      year         = {2025},
      note         = {2025 Feb 13;105(5):104107},
      abstract     = {FOLFIRI, a combination of folinic acid, 5-Fluorouracil, and
                      Irinotecan, is one of the recommended first-line
                      chemotherapeutic treatments for metastatic colorectal cancer
                      (mCRC). Unfortunately, acquired FOLFIRI resistance
                      represents a common obstacle in the treatment of mCRC
                      patients. Thus, we aimed to identify mechanisms, gene
                      alterations and gene expression signatures contributing to
                      acquired FOLFIRI resistance by mimicking this problem in a
                      cell culture model and subsequent translation in clinical
                      datasets. Three FOLFIRI resistant CRC cell lines were
                      established by continuous FOLFIRI treatment. Comparative
                      mutation screening (161 genes) and transcriptomics (pathway
                      and differential expression analyses) were performed in
                      parental and resistant cells. Data reconciliation was
                      performed in GSE62322, a clinical FOLFIRI responder dataset
                      (intrinsic resistance). Relapse-free survival (RFS)
                      associations of identified differentially expressed genes
                      (DEGs) and potential gene signatures were investigated in
                      eight clinical CRC datasets. No mutual genetic alterations
                      were found in FOLFIRI resistant derivatives. Resistant cell
                      lines displayed activation of MAPK, immune response and EMT
                      pathways. 12 DEGs, significantly differentially expressed in
                      at least two of the three resistant cell lines, were
                      identified. Comparison with GSE62322 and subsequent survival
                      analyses revealed a five-gene FOLFIRI signature comprised of
                      CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated
                      with RFS in multiple datasets including TCGA CRC (Hazard
                      ratio (HR)=2.634, p=4.53x10-6), in pooled samples of all
                      datasets (all stages (N=1981): HR=1.852, p=6.44x10-13; stage
                      IV (N=260): HR=2.462, p=5.22x10-9). A multivariate Cox
                      regression analysis identified the five-gene signature as an
                      independent prognostic factor in the TCGA dataset (HR=1.89,
                      p=0.0202). Our analyses revealed a five-gene FOLFIRI
                      resistance signature associated with RFS that may help to
                      predict FOLFIRI resistance and thus avoid unnecessary
                      ineffective treatment. Signature members might also
                      represent targets to fight FOLFIRI resistance.},
      keywords     = {FOLFIRI resistance (Other) / Metastatic colorectal cancer
                      (Other) / biomarker (Other) / gene signature (Other) /
                      survival (Other)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39954853},
      doi          = {10.1016/j.labinv.2025.104107},
      url          = {https://inrepo02.dkfz.de/record/298930},
}