title: Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions.
abstract: Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: D O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: R C
authors.initials: RC
authors.lastname: O'Hagan
authors.forename: D H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.forename: P A
authors.initials: PA
authors.lastname: Farazi
authors.forename: S
authors.initials: S
authors.lastname: Alson
authors.forename: J
authors.initials: J
authors.lastname: Fleming
authors.forename: C C
authors.initials: CC
authors.lastname: Morton
authors.forename: K
authors.initials: K
authors.lastname: Frank
authors.forename: L
authors.initials: L
authors.lastname: Chin
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002872:Chromosome Deletion; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics* / Q000502:physiology; D005347:Fibroblasts; D005784:Gene Amplification / Q000235:genetics*; D017353:Gene Deletion; D006579:Heterozygote; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016296:Mutagenesis / Q000235:genetics; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000607893:LIG4 protein, human; D025803:Tumor Suppressor Protein p14ARF; D011088:DNA Ligases; D000072481:DNA Ligase ATP