RESUMO
The mechanisms generating cancer-initiating mutations are not well understood. Sonic hedgehog (SHH) pathway activation is frequent in medulloblastoma (MB), with PTCH1 mutations being a common initiating event. Here we investigated the role of the developmental mitogen SHH in initiating carcinogenesis in the cells of origin: granule cell progenitors (GCPs). We delineate a molecular mechanism for tumor initiation in MB. Exposure of GCPs to Shh causes a distinct form of DNA replication stress, increasing both origin firing and fork velocity. Shh promotes DNA helicase loading and activation, with increased Cdc7-dependent origin firing. The S-phase duration is reduced and hyper-recombination occurs, causing copy number neutral loss of heterozygosity-a frequent event at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing reduces recombination and preneoplastic tumor formation in mice. Therefore, tissue-specific replication stress induced by Shh promotes loss of heterozygosity, which in tumor-prone Ptch1+/- GCPs results in loss of this tumor suppressor-an early cancer-initiating event.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Animais , Carcinogênese/genética , Neoplasias Cerebelares/genética , Replicação do DNA/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , CamundongosRESUMO
We report the case of a 23-year-old left-handed woman with medically intractable praxis-induced reflex seizures mainly precipitated by writing. Selective resection of subtle end-of-sulcus cortical dysplasia in the right inferior parietal lobule resulted in freedom from seizures. To the best of our knowledge, this is the first case of praxis-induced reflex seizures mainly precipitated by writing in which a focal lesion was found and treated successfully by surgery.