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@ARTICLE{Budczies:120516,
      author       = {J. Budczies$^*$ and G. Mechtersheimer and C. Denkert$^*$
                      and F. Klauschen and S. S. Mughal and P. Chudasama$^*$ and
                      M. Bockmayr and K. Jöhrens and V. Endris and A. Lier and F.
                      Lasitschka and R. Penzel and M. Dietel$^*$ and B. Brors$^*$
                      and S. Gröschel$^*$ and H. Glimm$^*$ and P. Schirmacher$^*$
                      and M. Renner and S. Fröhling$^*$ and A. Stenzinger$^*$},
      title        = {{PD}-{L}1 ({CD}274) copy number gain, expression, and
                      immune cell infiltration as candidate predictors for
                      response to immune checkpoint inhibitors in soft-tissue
                      sarcoma.},
      journal      = {OncoImmunology},
      volume       = {6},
      number       = {3},
      issn         = {2162-402X},
      address      = {Austin, Tex.},
      publisher    = {Landes Bioscience},
      reportid     = {DKFZ-2017-00945},
      pages        = {e1279777 -},
      year         = {2017},
      abstract     = {Soft-tissue sarcomas (STS) are rare malignancies that
                      account for $1\%$ of adult cancers and comprise more than 50
                      entities. Current therapeutic options for advanced-stage STS
                      are limited. Immune checkpoint inhibitors targeting the
                      PD-1/PD-L1 signaling axis are being explored as new
                      treatment modality in STS; however, the determinants of
                      response to these agents are largely unknown. Using the
                      sarcoma data set of The Cancer Genome Altas (TCGA) and an
                      independent cohort of untreated high-grade STS, we analyzed
                      DNA copy number status and mRNA expression of PD-L1 in a
                      total of 335 STS cases. Copy number gains (CNG) were
                      detected in 54 TCGA cases $(21.1\%),$ of which 21 $(8.2\%)$
                      harbored focal PD-L1 CNG and that were most prevalent in
                      myxofibrosarcoma $(35\%)$ and undifferentiated pleomorphic
                      sarcoma $(34\%).$ In the untreated high-grade STS cohort, we
                      detected CNG in six cases $(7.6\%).$ Analysis of
                      co-amplified genes identified a 5.6-Mb core region
                      comprising 27 genes, including JAK2. Patients with PD-L1 CNG
                      had higher PD-L1 expression compared with STS without CNG
                      (fold change, 1.8; p = 0.02), an effect that was most
                      pronounced in the setting of focal PD-L1 CNG (fold change,
                      3.0; p = 0.0027). STS with PD-L1 CNG showed a significantly
                      higher mutational load compared with tumors with a diploid
                      PD-L1 locus (median number of mutated genes; 58 vs. 40; p =
                      3.6E-06), and PD-L1 CNG were associated with inferior
                      survival (HR = 1.82; p = 0.025). In contrast, T-cell
                      infiltrates quantified by mRNA expression of CD3Z were
                      associated with improved survival (HR = 0.88; p = 0.024) and
                      consequently influenced the prognostic power of PD-L1 CNG,
                      with low CD3Z levels conferring poor survival in cases with
                      PD-L1 CNG (HR = 1.8; p = 0.049). These data demonstrate that
                      PD-L1 GNG and elevated expression of PD-L1 occur in a
                      substantial proportion of STS, have prognostic impact that
                      is modulated by T-cell infiltrates, and thus warrant
                      investigation as response predictors for immune checkpoint
                      inhibition.},
      cin          = {G100 / G200 / G240 / L201 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)G200-20160331 /
                      I:(DE-He78)G240-20160331 / I:(DE-He78)L201-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28405504},
      pmc          = {pmc:PMC5384369},
      doi          = {10.1080/2162402X.2017.1279777},
      url          = {https://inrepo02.dkfz.de/record/120516},
}