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, and 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 remarkable therapeutic target for first and second line combination treatments.

中文翻译：

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Pik3ca突变显着增强Shh髓母细胞瘤的生长，并在新型小鼠模型中导致转移性肿瘤生长。

髓母细胞瘤（MB）是预后不良的儿童中最常见的恶性脑肿瘤。声波刺猬（SHH）子集的MB分为四个分子亚组，约占病例总数的25％，并受SHH途径组分（例如其受体PTCH1或SMO）内突变的驱动。这些病例中有一部分还带有PIK3CA突变，其相关性目前尚不清楚。为了揭示Pik3ca突变单独或与组成型激活的SHH信号传导途径结合的作用，使用了转基因小鼠。这些小鼠显示小脑颗粒神经元前体中Smo，Ptch1和Pik3ca基因内的突变变体，这些基因代表SHH MB的细胞起源。我们的结果表明，单独的Pik3ca突变不足以引起发育改变或引发MB。然而，它们显着加速Shh MB的生长，诱导肿瘤扩散到整个脑脊液中，并导致具有双Pik3caH1047R / SmoM2或Pik3caH1047R / Ptch1突变的小鼠的存活率降低。因此，SHH MB中的PIK3CA突变可能代表一线和二线联合治疗的显着治疗靶标。