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@ARTICLE{Schallenberg:275482,
      author       = {S. Schallenberg and M.-P. Dragomir$^*$ and P. Anders and B.
                      Ebner and Y. Volz and L. Eismann and S. Rodler and J.
                      Casuscelli and A. Buchner and F. Klauschen$^*$ and C. Stief
                      and D. Horst$^*$ and G. B. Schulz},
      title        = {{I}ntratumoral {H}eterogeneity of {M}olecular {S}ubtypes in
                      {M}uscle-invasive {B}ladder {C}ancer-{A}n {E}xtensive
                      {M}ultiregional {I}mmunohistochemical {A}nalysis.},
      journal      = {European urology focus},
      volume       = {9},
      number       = {5},
      issn         = {2405-4569},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00789},
      pages        = {788-798},
      year         = {2023},
      note         = {2023 Sep;9(5):788-798},
      abstract     = {Molecular bladder cancer (BC) subtypes define distinct
                      biological entities and were shown to predict treatment
                      response in neoadjuvant and adjuvant settings. The extent of
                      intratumoral heterogeneity (ITH) might affect subtyping of
                      individual patients.To comprehensively assess the ITH of
                      molecular subtypes in a cohort of muscle-invasive BC.A total
                      of 251 patients undergoing radical cystectomy were screened.
                      Three cores of the tumor center (TC) and three cores of the
                      invasive tumor front (TF) of each patient were assembled in
                      a tissue microarray. Molecular subtypes were determined
                      employing 12 pre-evaluated immunohistochemical markers
                      (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3,
                      TUBB2B, EPCAM, CDH1, and vimentin). A total of 18 072 spots
                      were evaluated, of which 15 002 spots were assessed based on
                      intensity, distribution, or combination.Allocation to one of
                      five different molecular subtypes-urothelial like,
                      genomically unstable, small-cell/neuroendocrine like,
                      basal/squamous cell carcinoma like, and mesenchymal like-was
                      conducted for each patient for the complete tumor,
                      individual cores, TF, and TC separately. The primary
                      objective was to assess the ITH between the TF and TC (n =
                      208 patients). The secondary objective was the evaluation of
                      multiregion ITH (n = 191 patients). An analysis of the
                      composition of ITH cases, association with
                      clinicopathological parameters, and prognosis was
                      conducted.ITH between the TF and TC was seen in $12.5\%$ (n
                      = 26/208), and ITH defined by at least two different
                      subtypes of any location was seen in $24.6\%$ (n = 47/191).
                      ITH was more frequent in locally confined (pT2) versus
                      advanced (pT ≥3) BC stages $(38.7\%$ vs $21.9\%,$ p =
                      0.046), and pT4 BC presented with significantly more basal
                      subtypes than pT2 BC $(26.2\%$ vs $11.5\%,$ p = 0.049). In
                      our cohort, there was no association of subtype ITH with
                      prognosis or accumulation of specific molecular subtypes in
                      ITH cases. The key limitations were missing transcriptomic
                      and mutational genetic validation as well as investigation
                      of ITH beyond subtypes.Several molecular subtypes can be
                      found in nearly every fourth case of muscle-invasive BC,
                      when using immunohistochemistry. ITH must be given due
                      consideration for subtype-guided strategies in BC. Genomic
                      validation of these results is needed.Different molecular
                      subtypes can be found in many cases of muscle-invasive
                      bladder cancer. This might have implications for
                      individualized, subtype-based therapeutic approaches.},
      keywords     = {Bladder cancer (Other) / Immunohistochemistry (Other) /
                      Intratumoral heterogeneity (Other) / Molecular subtyping
                      (Other) / Urothelial carcinoma (Other)},
      cin          = {BE01 / MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331 / I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37076398},
      doi          = {10.1016/j.euf.2023.03.012},
      url          = {https://inrepo02.dkfz.de/record/275482},
}