% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Korshunov:180534,
      author       = {A. Korshunov$^*$ and K. Okonechnikov$^*$ and D. Stichel$^*$
                      and D. Schrimpf$^*$ and A. Delaidelli and S. Tonn and M.
                      Mynarek and P. Sievers$^*$ and F. Sahm$^*$ and D. Jones$^*$
                      and A. von Deimling$^*$ and S. Pfister$^*$ and M. Kool$^*$},
      title        = {{G}ene expression profiling of {G}roup 3 medulloblastomas
                      defines a clinically tractable stratification based on
                      {KIRREL}2 expression.},
      journal      = {Acta neuropathologica},
      volume       = {144},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2022-01396},
      pages        = {339–352},
      year         = {2022},
      note         = {#EA:B300#LA:B062# / 144, pages 339–352 (2022)},
      abstract     = {Medulloblastomas (MB) molecularly designated as Group 3
                      (Grp 3) MB represent a more clinically aggressive tumor
                      variant which, as a group, displays heterogeneous molecular
                      characteristics and disease outcomes. Reliable risk
                      stratification of Grp 3 MB would allow for appropriate
                      assignment of patients to aggressive treatment protocols
                      and, vice versa, for sparing adverse effects of high-dose
                      radio-chemotherapy in patients with standard or low-risk
                      tumors. Here we performed RNA-based analysis on an
                      international cohort of 179 molecularly designated Grp 3 MB
                      treated with HIT protocols. We analyzed the clinical
                      significance of differentially expressed genes, thereby
                      developing optimal prognostic subdivision of this MB
                      molecular group. We compared the transcriptome profiles of
                      two Grp 3 MB subsets with various outcomes (76 died within
                      the first 60 months vs. 103 survived this period) and
                      identified 224 differentially expressed genes (DEG) between
                      these two clinical groups (Limma R algorithm, adjusted
                      p-value < 0.05). We selected the top six DEG overexpressed
                      in the unfavorable cohort for further survival analysis and
                      found that expression of all six genes strongly correlated
                      with poor outcomes. However, only high expression of KIRREL2
                      was identified as an independent molecular prognostic
                      indicator of poor patients' survival. Based on clinical and
                      molecular patterns, four risk categories were outlined for
                      Grp 3 MB patients: i. low-risk: M0-1/MYC
                      non-amplified/KIRREL2 low (n = 48; 5-year $OS-95\%);$ ii.
                      standard-risk: M0-1/MYC non-amplified/KIRREL2 high or
                      M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year
                      $OS-70\%);$ iii. high-risk: M2-3/MYC non-amplified/KIRREL2
                      high (n = 36; 5-year $OS-30\%);$ iv. very high risk-all MYC
                      amplified tumors (n = 30; 5-year $OS-0\%).$ Cross-validated
                      survival models incorporating KIRREL2 expression with
                      clinical features allowed for the reclassification of up to
                      $50\%$ of Grp 3 MB patients into a more appropriate risk
                      category. Finally, KIRREL2 immunopositivity was also
                      identified as a predictive indicator of Grp 3 MB poor
                      survival, thus suggesting its application as a possible
                      prognostic marker in routine clinical settings. Our results
                      indicate that integration of KIRREL2 expression in risk
                      stratification models may improve Grp 3 MB outcome
                      prediction. Therefore, simple gene and/or protein expression
                      analyses for this molecular marker could be easily adopted
                      for Grp 3 MB prognostication and may help in assigning
                      patients to optimal therapeutic approaches in prospective
                      clinical trials.},
      keywords     = {Expression (Other) / Group 3 (Other) / KIRREL2 (Other) /
                      Medulloblastoma (Other) / Prognosis (Other)},
      cin          = {B300 / HD01 / B062 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35771282},
      doi          = {10.1007/s00401-022-02460-1},
      url          = {https://inrepo02.dkfz.de/record/180534},
}