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.
Joslin Diabetes Center, Boston, MA 02115, USA. Sarah.Wright@joslin.harvard.edu
Sarah M
SM
Wright
Yong H
YH
Woo
Travis L
TL
Alley
Bobbi-Jo
BJ
Shirley
Ellen C
EC
Akeson
Kathy J
KJ
Snow
Sarah A
SA
Maas
Rachel L
RL
Elwell
Oded
O
Foreman
Kevin D
KD
Mills
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