title: Numerical chromosomal instability mediates susceptibility to radiation treatment.
abstract: The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bakhoum
authors.affiliation: 1] Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA [2] Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kabeche
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wood
authors.affiliation: 1] Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA [2] Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Laucius
authors.affiliation: 1] Department of Neurological Surgery and the Brain Tumor Research Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Dian
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Radiology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Laughney
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Reynolds
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Louie
authors.affiliation: 1] Department of Neurological Surgery and the Brain Tumor Research Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.affiliation: Section of Radiation Oncology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Bassem I
authors.initials: BI
authors.lastname: Zaki
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Murnane
authors.affiliation: 1] Department of Neurological Surgery and the Brain Tumor Research Center, University of California San Francisco, San Francisco, California 94143, USA [2] Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Petritsch
authors.affiliation: 1] Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA [2] Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D043171:Chromosomal Instability; D019457:Chromosome Breakage; D020090:Chromosome Segregation; D005909:Glioblastoma / Q000235:genetics* / Q000532:radiotherapy; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015162:Micronucleus Tests; D008938:Mitosis / Q000235:genetics; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000532:radiotherapy*; D011839:Radiation, Ionizing