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@ARTICLE{Wang:275601,
      author       = {J. Z. Wang and V. Patil and J. Liu and H. Dogan$^*$ and G.
                      Tabatabai$^*$ and L. S. Yefet and F. Behling and E. Hoffman
                      and S. Bunda and R. Yakubov and R. Kaloti and S. Brandner
                      and A. Gao and A. Cohen-Gadol and J. Barnholtz-Sloan and M.
                      Skardelly and M. Tatagiba and D. R. Raleigh and F. Sahm$^*$
                      and P. C. Boutros and K. Aldape and F. Nassiri and G. Zadeh},
      collaboration = {I. C. o. Meningiomas},
      title        = {{I}ncreased m{RNA} expression of {CDKN}2{A} is a
                      transcriptomic marker of clinically aggressive meningiomas.},
      journal      = {Acta neuropathologica},
      volume       = {146},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2023-00811},
      pages        = {145-162},
      year         = {2023},
      note         = {2023 Jul;146(1):145-162},
      abstract     = {Homozygous deletion of CDKN2A/B was recently incorporated
                      into the World Health Organization classification for grade
                      3 meningiomas. While this marker is overall rare in
                      meningiomas, its relationship to other CDKN2A alterations on
                      a transcriptomic, epigenomic, and copy number level has not
                      yet been determined. We therefore utilized multidimensional
                      molecular data of 1577 meningioma samples from 6 independent
                      cohorts enriched for clinically aggressive meningiomas to
                      comprehensively interrogate the spectrum of CDKN2A
                      alterations through DNA methylation, copy number variation,
                      transcriptomics, and proteomics using an integrated
                      molecular approach. Homozygous CDKN2A/B deletions were
                      identified in only $7.1\%$ of cases but were associated with
                      significantly poorer outcomes compared to tumors without
                      these deletions. Heterozygous CDKN2A/B deletions were
                      identified in $2.6\%$ of cases and had similarly poor
                      outcomes as those with homozygous deletions. Among tumors
                      with intact CDKN2A/B (without a homozygous or heterozygous
                      deletion), we found a distinct difference in outcome based
                      on mRNA expression of CDKN2A, with meningiomas that had
                      elevated mRNA expression (CDKN2Ahigh) having a
                      significantly shorter time to recurrence. The expression of
                      CDKN2A was independently prognostic after accounting for
                      copy number loss and consistently increased with WHO grade
                      and more aggressive molecular and methylation groups
                      irrespective of cohort. Despite the discordant and mutually
                      exclusive status of the CDKN2A gene in these groups,
                      both CDKN2Ahigh meningiomas and meningiomas with CDKN2A
                      deletions were enriched for similar cell cycle pathways but
                      at different checkpoints. High mRNA expression of CDKN2A was
                      also associated with gene hypermethylation, Rb-deficiency,
                      and lack of response to CDK inhibition. p16
                      immunohistochemistry could not reliably differentiate
                      between meningiomas with and without CDKN2A deletions but
                      appeared to correlate better with mRNA expression. These
                      findings support the role of CDKN2A mRNA expression as a
                      biomarker of clinically aggressive meningiomas with
                      potential therapeutic implications.},
      keywords     = {CDK inhibitor (Other) / CDKN2A (Other) / Copy number
                      alterations (Other) / Meningiomas (Other) / Multiomic
                      (Other) / Retinoblastoma (Other)},
      cin          = {B300 / TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)TU01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37093270},
      doi          = {10.1007/s00401-023-02571-3},
      url          = {https://inrepo02.dkfz.de/record/275601},
}