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@ARTICLE{Menzel:276893,
      author       = {M. Menzel and V. Endris and C. Schwab and K. Kluck and O.
                      Neumann and S. Beck and M. Ball and C. Schaaf and S.
                      Fröhling$^*$ and P. Lichtner and P. Schirmacher$^*$ and D.
                      Kazdal and A. Stenzinger$^*$ and J. Budczies$^*$},
      title        = {{A}ccurate tumor purity determination is critical for the
                      analysis of homologous recombination deficiency ({HRD}).},
      journal      = {Translational oncology},
      volume       = {35},
      issn         = {1944-7124},
      address      = {Ann Arbor, Mich.},
      publisher    = {[Verlag nicht ermittelbar]},
      reportid     = {DKFZ-2023-01195},
      pages        = {101706},
      year         = {2023},
      abstract     = {Homologous recombination deficiency (HRD) is a predictive
                      marker for response to poly (ADP-ribose) polymerase
                      inhibitors (PARPi) in ovarian carcinoma. HRD scores have
                      entered routine diagnostics, but the influence of
                      algorithms, parameters and confounders has not been analyzed
                      comprehensively. A series of 100 poorly differentiated
                      ovarian carcinoma samples was analyzed using whole exome
                      sequencing (WES) and genotyping. Tumor purity was determined
                      using conventional pathology, digital pathology, and two
                      bioinformatic methods. HRD scores were calculated from copy
                      number profiles determined by Sequenza and by Sclust either
                      with or without fixed tumor purity. Tumor purity
                      determination by digital pathology combined with a tumory
                      purity informed variant of Sequenza served as reference
                      method for HRD scoring. Seven tumors had deleterious
                      mutations in BRCA1/2, 12 tumors had deleterious mutations in
                      other homologous recombination repair (HRR) genes, 18 tumors
                      had variants of unknown significance (VUS) in BRCA1/2 or
                      other HRR genes, while the remaining 63 tumors had no
                      relevant alterations. Using the reference method for HRD
                      scoring, 68 tumors were HRD-positive. HRDsum determined by
                      WES correlated strongly with HRDsum determined by single
                      nucleotide polymorphism (SNP) arrays (R = 0.85).
                      Conventional pathology systematically overestimated tumor
                      purity by $8\%$ compared to digital pathology. All
                      investigated methods agreed on classifying the deleterious
                      BRCA1/2-mutated tumors as HRD-positive, but discrepancies
                      were observed for some of the remaining tumors. Discordant
                      HRD classification of $11\%$ of the tumors was observed
                      comparing the tumor purity uninformed default of Sequenza
                      and the reference method. In conclusion, tumor purity is a
                      critical factor for the determination of HRD scores.
                      Assistance by digital pathology helps to improve accuracy
                      and imprecision of its estimation.},
      keywords     = {HRD (Other) / Homologous recombination deficiency (Other) /
                      Tumor cell content (Other) / Tumor purity (Other) / WES
                      (Other) / Whole exome sequencing (Other)},
      cin          = {HD01 / B340},
      ddc          = {610},
      cid          = {I:(DE-He78)HD01-20160331 / I:(DE-He78)B340-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37327584},
      doi          = {10.1016/j.tranon.2023.101706},
      url          = {https://inrepo02.dkfz.de/record/276893},
}