Klin Padiatr 2018; 230(03): 170
DOI: 10.1055/s-0038-1645005
Top 3 Solid tumors
Georg Thieme Verlag KG Stuttgart · New York

PIK3CA mutations significantly enhance the growth of Shh medulloblastoma

J Niesen
1   Research Institute Children's Cancer Center, Hamburg
2   Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf
,
J Ohli
3   Center of Neuropathology, Ludwig-Maximilians-University, Munich
,
U Schüller
1   Research Institute Children's Cancer Center, Hamburg
2   Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf
4   Institute of Neuropathology, Hamburg
› Author Affiliations
Further Information

Publication History

Publication Date:
08 May 2018 (online)

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Background:

Medulloblastoma (MB), the most frequent malignant brain tumor in children, is divided into 4 subgroups with MB of the SHH subtype as best analyzed one. Standard radio- and chemotherapy is often left with severe side effects, and the younger the patient, the worse the long-term effects are. Therefore, targeted treatment options are urgently needed. Drugs targeting the Shh pathway (SMO-antagonists) show resistance and heterogeneous responses. In order to identify novel targets, this project works on frequency, distribution and function of PIK3CA mutations in MB.

Methods:

Whole genome sequencing data were analyzed to define the incidence of PIK3CA mutations in MB. Transgenic mouse models were generated to demonstrate the role of PIK3CA H1047R mutations alone or in combination with a constitutively activated Shh signaling pathway (using lox-Stop-lox-SmoM2 or Ptch1 Fl/Fl alleles). All mice were analyzed by immunohistochemical methods and survival was estimated.

Results:

PIK3CA mutations occur in all subgroups with the highest frequency in SHH MB, typically in combination with SMO or PTCH1 mutations. Activation of PI3-kinase-signaling pathway in Math1-positive cerebellar granule neuron precursors is not sufficient for tumor development. Shh MB growth was detected in Math1-creERT2::lsl-SmoM2 or Math1-creERT2::Ptch1 Fl/Fl mice and significantly enhanced by additional PIK3CA H1047R mutation.

Conclusions:

PIK3CA mutations represent frequent alterations in MB, particularly in SHH MB. They seem to contribute to MB tumor growth and may therefore be used as a new therapeutic target.