Frappart Pierre-Olivier, Lee Youngsoo, Russell Helen R, Chalhoub Nader, Wang Yong-Dong, Orii Kenji E, Zhao Jingfeng, Kondo Naomi, Baker Suzanne J, McKinnon Peter J
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1880-5. doi: 10.1073/pnas.0806882106. Epub 2009 Jan 21.
Inactivation of homologous recombination (HR) or nonhomologous end-joining (NHEJ) predisposes to a spectrum of tumor types. Here, we inactivated DNA double-strand break repair (DSBR) proteins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/Xrcc2 during neural development using Nestin-cre. In all cases, inactivation of these repair factors, together with p53 loss, led to rapid medulloblastoma formation. Genomic analysis of these tumors showed recurring chromosome 13 alterations via chromosomal loss or translocations involving regions containing Ptch1. Sequence analysis of the remaining Ptch1 allele showed a variety of inactivating mutations in all tumors analyzed, highlighting the critical tumor suppressor function of this hedgehog-signaling regulator. We also observed genomic amplification or up-regulation of either N-Myc or cyclin D2 in all medulloblastomas. Additionally, chromosome 19, which contains Pten, was also selectively deleted in medulloblastoma arising after disruption of HR. Thus, our data highlight the preeminence of Ptch1 as a tumor suppressor in cerebellar granule cells and reveal other genomic events central to the genesis of medulloblastoma.
同源重组（HR）或非同源末端连接（NHEJ）的失活易引发一系列肿瘤类型。在此，我们利用巢蛋白-Cre在神经发育过程中使DNA双链断裂修复（DSBR）蛋白、DNA连接酶IV（Lig4）、Xrcc2和Brca2失活，或使Lig4/Xrcc2联合失活。在所有情况下，这些修复因子的失活与p53缺失共同作用，导致快速形成髓母细胞瘤。对这些肿瘤的基因组分析显示，通过染色体缺失或涉及包含Ptch1区域的易位，13号染色体出现反复改变。对剩余Ptch1等位基因的序列分析表明，在所有分析的肿瘤中均存在多种失活突变，突出了这种刺猬信号调节因子的关键肿瘤抑制功能。我们还在所有髓母细胞瘤中观察到N-Myc或细胞周期蛋白D2的基因组扩增或上调。此外，在HR破坏后产生的髓母细胞瘤中，包含Pten的19号染色体也被选择性删除。因此，我们的数据突出了Ptch1作为小脑颗粒细胞肿瘤抑制因子的卓越地位，并揭示了髓母细胞瘤发生过程中其他关键的基因组事件。
