Complex oncogenic translocations with gene amplification are initiated by specific DNA breaks in lymphocytes.
Chromosomal instability is a hallmark of many tumor types. Complex chromosomal rearrangements with associated gene amplification, known as complicons, characterize many hematologic and solid cancers. Whereas chromosomal aberrations, including complicons, are useful diagnostic and prognostic cancer markers, their molecular origins are not known. Although accumulating evidence has implicated DNA double-strand break repair in suppression of oncogenic genome instability, the genomic elements required for chromosome rearrangements, especially complex lesions, have not been elucidated. Using a mouse model of B-lineage lymphoma, characterized by complicon formation involving the immunoglobulin heavy chain (Igh) locus and the c-myc oncogene, we have now investigated the requirement for specific genomic segments as donors for complex rearrangements. We now show that specific DNA double-strand breaks, occurring within a narrow segment of Igh, are necessary to initiate complicon formation. By contrast, neither specific DNA breaks nor the powerful intronic enhancer Emu are required for complicon-independent oncogenesis. This study is the first to delineate mechanisms of complex versus simple instability and the first to identify specific chromosomal elements required for complex chromosomal aberrations. These findings will illuminate genomic cancer susceptibility and risk factors.
Wright
Sarah M
SM
Joslin Diabetes Center, Boston, MA 02115, USA. Sarah.Wright@joslin.harvard.edu
Woo
Yong H
YH
Alley
Travis L
TL
Shirley
Bobbi-Jo
BJ
Akeson
Ellen C
EC
Snow
Kathy J
KJ
Maas
Sarah A
SA
Elwell
Rachel L
RL
Foreman
Oded
O
Mills
Kevin D
KD
D000818:Animals; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D005784:Gene Amplification; D015321:Gene Rearrangement; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D008214:Lymphocytes / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D051379:Mice; D012307:Risk Factors; D014178:Translocation, Genetic
D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region