Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency.
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.
Frappart
Pierre-Olivier
PO
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lee
Youngsoo
Y
Russell
Helen R
HR
Chalhoub
Nader
N
Wang
Yong-Dong
YD
Orii
Kenji E
KE
Zhao
Jingfeng
J
Kondo
Naomi
N
Baker
Suzanne J
SJ
McKinnon
Peter J
PJ
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair; D049914:DNA Repair-Deficiency Disorders / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D042822:Genomic Instability; D008527:Medulloblastoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D025521:Tumor Suppressor Proteins
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C491866:Xrcc2 protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP