Evidence for a novel mechanism for gene amplification in multiple myeloma: 1q12 pericentromeric heterochromatin mediates breakage-fusion-bridge cycles of a 1q12 approximately 23 amplicon.
Gene amplification is defined as a copy number (CN) increase in a restricted region of a chromosome arm, and is a mechanism for acquired drug resistance and oncogene activation. In multiple myeloma (MM), high CNs of genes in a 1q12 approximately 23 amplicon have been associated with disease progression and poor prognosis. To investigate the mechanisms for gene amplification in this region in MM, we performed a comprehensive metaphase analysis combining G-banding, fluorescence in situ hybridization, and spectral karyotyping in 67 patients with gain of 1q. In six patients (9%), evidence for at least one breakage-fusion-bridge (BFB) cycle was found. In three patients (4%), extended ladders of 1q12 approximately 23 amplicons were identified. Several key structures that are predicted intermediates in BFB cycles were observed, including: equal-spaced organization of amplicons, inverted repeat organization of amplicons along the same chromosome arm, and deletion of sequences distal to the amplified region. The 1q12 pericentromeric heterochromatin region served as both a recurrent breakpoint as well as a fusion point for sister chromatids, and ultimately bracketed both the proximal and distal boundaries of the amplicon. Our findings provide evidence for a novel BFB mechanism involving 1q12 pericentromeric breakage in the amplification of a large number of genes within a 1q12 approximately 23 amplicon.
Sawyer
Jeffrey R
JR
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72204, USA. sawyerjeffreyr@uams.edu
Tian
Erming
E
Thomas
Edward
E
Koller
Mark
M
Stangeby
Colin
C
Sammartino
Gael
G
Goosen
Linda
L
Swanson
Charles
C
Binz
Regina L
RL
Barlogie
Bart
B
Shaughnessy
John
J
D019457:Chromosome Breakage; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D007621:Karyotyping; D009101:Multiple Myeloma / Q000235:genetics*
D006570:Heterochromatin