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Published online on May 2, 2006, 10.1073/pnas.0601938103

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Genetics
XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice

Catherine T. Yan *{dagger}{ddagger}, Dhruv Kaushal *{dagger}, Michael Murphy *{dagger}, Yu Zhang *{dagger}, Abhishek Datta *{dagger}, Changzhong Chen {sect}, Brianna Monroe *{dagger}, Gustavo Mostoslavsky {dagger}, Kristen Coakley *{dagger}, Yijie Gao *{dagger}¶, Kevin D. Mills *{dagger}||, Alex P. Fazeli *{dagger}, Suprawee Tepsuporn *{dagger}, Giles Hall {sect}, Richard Mulligan {dagger}, Edward Fox {sect}, Roderick Bronson **, Umberto De Girolami {dagger}{dagger}, Charles Lee **{ddagger}{ddagger}, and Frederick W. Alt *{dagger}{sect}{sect}

*Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Departments of {dagger}Genetics, {ddagger}Pediatrics, and **Pathology, Harvard Medical School, Boston, MA 02115; {ddagger}{ddagger}Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; {dagger}{dagger}Department of Neuropathology, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA 02115; and {sect}Dana-Farber Microarray Core Facility, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115

Contributed by Frederick W. Alt, March 10, 2006

Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.

Author contributions: C.T.Y. and M.M. designed research; C.T.Y., D.K., M.M., Y.Z., A.D., B.M., G.M., K.C., K.D.M., A.P.F., S.T., R.M., and C.L. performed research; C.T.Y., Y.Z., C.C., Y.G., G.H., E.F., U.D.G., and C.L. contributed new reagents/analytic tools; C.T.Y., D.K., M.M., Y.Z., A.D., C.C., R.B., U.D.G., and C.L. analyzed data; and C.T.Y., D.K., and F.W.A. wrote the paper.

Conflict of interest statement: No conflicts declared.

Present address: Wyeth Pharmaceutical, Cambridge Park Drive, Cambridge, MA 02140.

||Present address: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609.

{sect}{sect}To whom correspondence should be addressed.

Frederick W. Alt, E-mail: alt{at}enders.tch.harvard.edu

www.pnas.org/cgi/doi/10.1073/pnas.0601938103
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