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@ARTICLE{Rautajoki:285254,
      author       = {K. J. Rautajoki and S. Jaatinen and A. Hartewig and A. M.
                      Tiihonen and M. Annala and I. Salonen and M. Valkonen and V.
                      Simola and E. M. Vuorinen and A. Kivinen and M. J. Rauhala
                      and R. Nurminen and K. K. Maass$^*$ and S.-L. Lahtela and A.
                      Jukkola and O. Yli-Harja and P. Helén and K. W. Pajtler$^*$
                      and P. Ruusuvuori and J. Haapasalo and W. Zhang and H.
                      Haapasalo and M. Nykter},
      title        = {{G}enomic characterization of {IDH}-mutant astrocytoma
                      progression to grade 4 in the treatment setting.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {11},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2023-02289},
      pages        = {176},
      year         = {2023},
      abstract     = {As the progression of low-grade diffuse astrocytomas into
                      grade 4 tumors significantly impacts patient prognosis, a
                      better understanding of this process is of paramount
                      importance for improved patient care. In this project, we
                      analyzed matched IDH-mutant astrocytomas before and after
                      progression to grade 4 from six patients (discovery cohort)
                      with genome-wide sequencing, 21 additional patients with
                      targeted sequencing, and 33 patients from Glioma
                      Longitudinal AnalySiS cohort for validation. The Cancer
                      Genome Atlas data from 595 diffuse gliomas provided
                      supportive information. All patients in our discovery cohort
                      received radiation, all but one underwent chemotherapy, and
                      no patient received temozolomide (TMZ) before progression to
                      grade 4 disease. One case in the discovery cohort exhibited
                      a hypermutation signature associated with the inactivation
                      of the MSH2 and DNMT3A genes. In other patients, the number
                      of chromosomal rearrangements and deletions increased in
                      grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or
                      less frequently RB1, was most commonly inactivated after
                      receiving both chemo- and radiotherapy when compared to
                      other treatment groups. Concomitant activating PDGFRA/MET
                      alterations were detected in tumors that acquired a
                      homozygous CDKN2A deletion. NRG3 gene was significantly
                      downregulated and recurrently altered in progressed tumors.
                      Its decreased expression was associated with poorer overall
                      survival in both univariate and multivariate analysis. We
                      also detected progression-related alterations in RAD51B and
                      other DNA repair pathway genes associated with the promotion
                      of error-prone DNA repair, potentially facilitating tumor
                      progression. In our retrospective analysis of patient
                      treatment and survival timelines (n = 75), the combination
                      of postoperative radiation and chemotherapy (mainly TMZ)
                      outperformed radiation, especially in the grade 3 tumor
                      cohort, in which it was typically given after primary
                      surgery. Our results provide further insight into the
                      contribution of treatment and genetic alterations in cell
                      cycle, growth factor signaling, and DNA repair-related genes
                      to tumor evolution and progression.},
      keywords     = {Cancer genomics (Other) / Diffuse glioma (Other) /
                      Homologous recombination repair (Other) / Longitudinal
                      analysis (Other) / Microhomology-mediated end-joining
                      (Other) / Non-homologous end-joining (Other) /
                      RNA-sequencing (Other) / Secondary glioblastoma (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / 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:37932833},
      doi          = {10.1186/s40478-023-01669-9},
      url          = {https://inrepo02.dkfz.de/record/285254},
}