Telomere dysfunction provokes regional amplification and deletion in cancer genomes.
Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Rónán C
RC
O'Hagan
Sandy
S
Chang
Richard S
RS
Maser
Ramya
R
Mohan
Steven E
SE
Artandi
Lynda
L
Chin
Ronald A
RA
DePinho
D000818:Animals; D002869:Chromosome Aberrations; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D016158:Genes, p53; D016678:Genome; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D012313:RNA / Q000235:genetics; D026801:Synteny; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
D004273:DNA, Neoplasm; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase