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.

产生癌症起始突变的机制尚不清楚。Sonic Hedgehog (SHH) 通路激活在髓母细胞瘤 (MB) 中很常见，其中PTCH1突变是常见的起始事件。在这里，我们研究了发育有丝分裂原 SHH 在起始细胞中的致癌作用：颗粒细胞祖细胞 (GCP)。我们描述了MB中肿瘤起始的分子机制。将 GCP 暴露于 Shh 会导致一种不同形式的 DNA 复制压力，从而增加起源发射和分叉速度。Shh 促进 DNA 解旋酶加载和激活，增加了 Cdc7 依赖的起源放电。S 期持续时间缩短并发生超重组，导致杂合性的拷贝数中性丢失——PTCH1/ptch1的常见事件轨迹。此外，抑制 Cdc7 以减弱起源放电可减少小鼠的重组和肿瘤前肿瘤的形成。因此，由 Shh 诱导的组织特异性复制应激会促进杂合性的丧失，这在易患肿瘤的Ptch1 ^+/- GCP 中会导致这种肿瘤抑制因子的丧失——这是一种早期的癌症起始事件。