Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity.
Telomere dysfunction has been associated with chromosomal instability in colorectal carcinoma, but the consequences of telomere-dependent instability for chromosome integrity and clonal evolution have been little explored. We show here that abnormally short telomeres lead to a wide spectrum of mitotic disturbances in colorectal cancer cell lines, including anaphase bridging, whole-chromosome lagging, and mitotic multipolarity. These abnormalities were found in both the presence and absence of microsatellite instability. The mean telomere length varied extensively between cells from the same tumor, allowing the establishment of tumor cell subpopulations with highly different frequencies of mitotic disturbances. Anaphase bridging typically resulted in either inter-centromeric chromatin fragmentation or centromere detachment, leading to pericentromeric chromosome rearrangements and loss of whole chromosomes, respectively. There was a strong correlation between anaphase bridges and multipolar mitoses, and the induction of dicentric chromosomes by gamma irradiation and telomerase inhibition led to an elevated frequency of multipolar mitotic spindles, suggesting that multipolarity could result from polyploidization triggered by anaphase bridging. Chromatid segregation in multipolar mitoses was close to random, resulting in frequent nullisomies and nonviable daughter cells. In contrast, there was a high clonogenic survival among cells having gone through anaphase bridging in bipolar mitoses. Bridging of telomere-deficient chromosomes could thus be a major mutational mechanism in colorectal cancer, whereas mitotic multipolarity appears to be a secondary phenomenon that rarely, if ever, contributes to clonal evolution.
Stewénius
Ylva
Y
Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden.
Gorunova
Ludmila
L
Jonson
Tord
T
Larsson
Nina
N
Höglund
Mattias
M
Mandahl
Nils
N
Mertens
Fredrik
F
Mitelman
Felix
F
Gisselsson
David
D
D000705:Anaphase; D000782:Aneuploidy; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D019457:Chromosome Breakage / Q000235:genetics; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008938:Mitosis; D016296:Mutagenesis / Q000235:genetics; D011123:Polyploidy; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin