Molecular characterization of medulloblastomas with extensive nodularity (MBEN)

  • Andrey Korshunov
  • Felix Sahm
  • Damian Stichel
  • Daniel Schrimpf
  • Marina Ryzhova
  • Olga Zheludkova
  • Andrey Golanov
  • Peter Lichter
  • David T. W. Jones
  • Andreas von Deimling
  • Stefan M. Pfister
  • Marcel Kool
Original Paper

Abstract

Medulloblastoma with extensive nodularity (MBEN) is a rare histological variant of medulloblastoma (MB). These tumors are usually occurring in the first 3 years of life and are associated with good prognosis. Molecular analyses of MBEN, mostly limited to single cases or small series, have shown that they always classify as sonic hedgehog (SHH)-driven MB. Here, we have analyzed 25 MBEN through genome-wide DNA methylation, copy-number profiling and targeted next-generation sequencing. Results of these analyses were compared with molecular profiles of other SHH MB histological variants. As expected, the vast majority of MBEN (23/25) disclosed SHH-associated epigenetic signatures and mutational landscapes but, surprisingly, two MBEN were classified as Group 3/4 MB. Most MBEN classified as SHH MB displayed SHH-related and mutually exclusive mutations in either SUFU, or PTCH1, or SMO at similar frequencies. However, only SUFU mutations were also identified in the germ-line. Most of SUFU-associated MBEN eventually recurred but patients were treated successfully with second-line high-dose chemotherapy. Altogether, our data show that risk stratification even for well-recognizable histologies such as MBEN cannot rely on histology alone but should include additional molecular analyses such as methylation profiling and DNA sequencing. For all patients with “MBEN” histology, we recommend sequencing SUFU and PTCH1 in the tumor as well as in the germ-line for further clinical stratification and choice of the optimal treatment strategy upfront.

Keywords

Medulloblastoma MBEN SHH MB SUFU 

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Andrey Korshunov
    • 1
    • 2
    • 3
  • Felix Sahm
    • 1
    • 2
    • 3
  • Damian Stichel
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • Marina Ryzhova
    • 4
  • Olga Zheludkova
    • 8
  • Andrey Golanov
    • 9
  • Peter Lichter
    • 3
    • 5
  • David T. W. Jones
    • 3
    • 6
  • Andreas von Deimling
    • 1
    • 2
    • 3
  • Stefan M. Pfister
    • 3
    • 6
    • 7
  • Marcel Kool
    • 3
    • 6
  1. 1.Clinical Cooperation Unit Neuropathology (G380)German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany
  2. 2.Department of NeuropathologyHeidelberg University HospitalHeidelbergGermany
  3. 3.Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  4. 4.Department of NeuropathologyNN Burdenko Neurosurgical InstituteMoscowRussia
  5. 5.Division of Molecular Genetics (B060)German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany
  6. 6.Division of Pediatric Neurooncology (B062)German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany
  7. 7.Department of Pediatric Hematology and OncologyHeidelberg University HospitalHeidelbergGermany
  8. 8.Department of Neuro-OncologyRussian Scientific Center of RadiologyMoscowRussia
  9. 9.Department of NeuroradiologyNN Burdenko Neurosurgical InstituteMoscowRussia

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