Department of Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Research Institute Children's Cancer Centre Hamburg, Hamburg, Germany.
Centre for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
Cancer Lett. 2020 May 1;477:10-18. doi: 10.1016/j.canlet.2020.02.028. Epub 2020 Feb 26.
Medulloblastoma (MB) is the most frequent malignant brain tumour in children with a poor outcome. Divided into four molecular subgroups, MB of the Sonic hedgehog (SHH) subgroup accounts for approximately 25% of the cases and is driven by mutations within components of the SHH pathway, such as its receptors PTCH1 or SMO. A fraction of these cases additionally harbour PIK3CA mutations, the relevance of which is so far unknown. To unravel the role of Pik3ca mutations alone or in combination with a constitutively activated SHH signalling pathway, transgenic mice were used. These mice show mutated variants within Smo, Ptch1 or Pik3ca genes in cerebellar granule neuron precursors, which represent the cellular origin of SHH MB. Our results show that Pik3ca mutations alone are insufficient to cause developmental alterations or to initiate MB. However, they significantly accelerate the growth of Shh MB, induce tumour spread throughout the cerebrospinal fluid, and result in lower survival rates of mice with a double Pik3caH1047R/SmoM2 or Pik3caH1047R/Ptch1 mutation. Therefore, PIK3CA mutations in SHH MB may represent a therapeutic target for first and second line combination treatments.
髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤，预后不良。MB 分为四个分子亚组，其中 Sonic hedgehog（SHH）亚组约占 25%，由 SHH 通路的组成部分（如其受体 PTCH1 或 SMO）的突变驱动。这些病例中有一部分还存在 PIK3CA 突变，其相关性目前尚不清楚。为了阐明 Pik3ca 突变单独或与持续激活的 SHH 信号通路结合的作用，使用了转基因小鼠。这些小鼠在小脑颗粒神经元前体细胞中显示 Smo、Ptch1 或 Pik3ca 基因的突变变异，这是 SHH MB 的细胞起源。我们的研究结果表明，Pik3ca 突变本身不足以引起发育改变或引发 MB。然而，它们显著加速了 Shh MB 的生长，诱导肿瘤在脑脊液中扩散，并导致具有双重 Pik3caH1047R/SmoM2 或 Pik3caH1047R/Ptch1 突变的小鼠的存活率降低。因此，SHH MB 中的 PIK3CA 突变可能成为一线和二线联合治疗的治疗靶点。
