breakrepairdeficiency.PDFVIP

Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency Pierre-Olivier Frapparta,1, Youngsoo Leea,1, Helen R. Russella, Nader Chalhoubb, Yong-Dong Wangc, Kenji E. Oriia,d, Jingfeng Zhaoa, Naomi Kondod, Suzanne J. Bakerb, and Peter J. McKinnona,2 Departments of aGenetics and Tumor Cell Biology and bDevelopmental Neurobiology, and cHartwell Center for Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and dDepartment of Pediatrics, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan Edited by James E. Cleaver, University of California, San Francisco, CA, and approved December 9, 2008 (received for review July 16, 2008) Inactivation of homologous recombination (HR) or nonhomolo- including PTCH1, SUFU, SMOH, or the Wingless (WNT) pathway, gous end-joining (NHEJ) predisposes to a spectrum of tumor types. such as AXIN1 or ?-CATENIN, have also been found in sporadic Here, we inactivated DNA double-strand break repair (DSBR) pro- human medulloblastomas, highlighting the importance of these teins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/ pathways for preventing cancer (16). Although mutations of the p53 Xrcc2 during neural development using Nestin-cre. In all cases, pathway occur in sporadic medulloblastomas (?20%), inactivation inactivation of these repair factors, together with p53 loss, led to of the p53 pathway may be prevalent (9, 14, 17, 18). rapid medulloblastoma formation. Genomic analysis of these tu- Consistent with the above, 5–15% of Ptch1 heterozygote mice mors showed recurring chromosome 13 alterations via chromo- develop medulloblastoma by 8 months of age (depending on the somal loss or translocations involving regions containing Ptch1. genetic background), an event that is associated with inactivation Sequence analysis of the remaining Ptch1 allele showed a variety of the remaining Ptch1 allele (19–21). Loss of p53 or Ptch2 of inactivating