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@ARTICLE{Suwala:165986,
      author       = {A. K. Suwala$^*$ and D. Stichel$^*$ and D. Schrimpf$^*$ and
                      M. Kloor$^*$ and A. K. Wefers$^*$ and A. Reinhardt$^*$ and
                      S. L. N. Maas and C. P. Kratz and L. Schweizer$^*$ and M.
                      Hasselblatt and M. Snuderl and M. S. J. Abedalthagafi and Z.
                      Abdullaev and C. M. Monoranu and M. Bergmann and A. Pekrun
                      and C. Freyschlag and E. Aronica and C. M. Kramm and F.
                      Hinz$^*$ and P. Sievers$^*$ and A. Korshunov$^*$ and M.
                      Kool$^*$ and S. M. Pfister$^*$ and D. Sturm$^*$ and D. T. W.
                      Jones$^*$ and W. Wick$^*$ and A. Unterberg and C. Hartmann
                      and A. Dodgshun and U. Tabori and P. Wesseling and F.
                      Sahm$^*$ and A. von Deimling$^*$ and D. Reuß$^*$},
      title        = {{P}rimary mismatch repair deficient {IDH}-mutant
                      astrocytoma ({PMMRDIA}) is a distinct type with a poor
                      prognosis.},
      journal      = {Acta neuropathologica},
      volume       = {141},
      number       = {1},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2020-02525},
      pages        = {85-100},
      year         = {2021},
      note         = {#EA:B300#LA:B300#2021 Jan;141(1):85-100},
      abstract     = {Diffuse IDH-mutant astrocytoma mostly occurs in adults and
                      carries a favorable prognosis compared to IDH-wildtype
                      malignant gliomas. Acquired mismatch repair deficiency is
                      known to occur in recurrent IDH-mutant gliomas as resistance
                      mechanism towards alkylating chemotherapy. In this
                      multi-institutional study, we report a novel epigenetic
                      group of 32 IDH-mutant gliomas with proven or suspected
                      hereditary mismatch repair deficiency. None of the tumors
                      exhibited a combined 1p/19q deletion. These primary mismatch
                      repair-deficient IDH-mutant astrocytomas (PMMRDIA) were
                      histologically high-grade and were mainly found in children,
                      adolescents and young adults (median age 14 years).
                      Mismatch repair deficiency syndromes (Lynch or
                      Constitutional Mismatch Repair Deficiency Syndrom (CMMRD))
                      were clinically diagnosed and/or germline mutations in DNA
                      mismatch repair genes (MLH1, MSH6, MSH2) were found in all
                      cases, except one case with a family and personal history of
                      colon cancer and another case with MSH6-deficiency available
                      only as recurrent tumor. Loss of at least one of the
                      mismatch repair proteins was detected via
                      immunohistochemistry in all, but one case analyzed. Tumors
                      displayed a hypermutant genotype and microsatellite
                      instability was present in more than half of the sequenced
                      cases. Integrated somatic mutational and chromosomal copy
                      number analyses showed frequent inactivation of TP53, RB1
                      and activation of RTK/PI3K/AKT pathways. In contrast to the
                      majority of IDH-mutant gliomas, more than $60\%$ of the
                      samples in our cohort presented with an unmethylated MGMT
                      promoter. While the rate of immuno-histochemical ATRX loss
                      was reduced, variants of unknown significance were more
                      frequently detected possibly indicating a higher frequency
                      of ATRX inactivation by protein malfunction. Compared to
                      reference cohorts of other IDH-mutant gliomas, primary
                      mismatch repair-deficient IDH-mutant astrocytomas have by
                      far the worst clinical outcome with a median survival of
                      only 15 months irrespective of histological or molecular
                      features. The findings reveal a so far unknown entity of
                      IDH-mutant astrocytoma with high prognostic relevance.
                      Diagnosis can be established by aligning with the
                      characteristic DNA methylation profile, by
                      DNA-sequencing-based proof of mismatch repair deficiency or
                      immunohistochemically demonstrating loss-of-mismatch repair
                      proteins.},
      cin          = {B300 / HD01 / F210 / BE01 / B062 / B360 / B320},
      ddc          = {610},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)F210-20160331 / I:(DE-He78)BE01-20160331 /
                      I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)B320-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33216206},
      doi          = {10.1007/s00401-020-02243-6},
      url          = {https://inrepo02.dkfz.de/record/165986},
}