Abstract
Abstract 298
MM is characterized by complex chromosome 1 aberrations including an unbalanced rearrangement known as a jumping translocation 1q12 (JT1q12). The JT1q12 is a chromosomal mechanism for arm-length amplification of 1q by the duplication of copies of 1q onto one or more non-homologous chromosomes. Two types of JT1q12 usually occur: one results in the translocation of the entire 1q to the telomere of a RC, increasing the CN of genes on the entire 1q. The second type of JT1q12 results from a whole-arm unbalanced (arm-length) translocation which increases the CN of genes on 1q, while at the same time decreasing the CN of genes on the RC. An increase in CN of 1q21 in MM has been reported to be associated with disease progression and poor prognosis. An alternative mechanism for CN alterations of 1q21 is also known that includes the focal amplification of a 1q12∼23 amplicon, which includes the genes MCL1, BCL9, IL6R, MUC1, PSMD4, and CKS1B, among others. In fact, focal amplifications of 1q21 and other genomic regions have recently been found to be shared across multiple cancer types, suggesting common amplification targets in the cancer genome (Nature, 463: 899–905, 2010). Unfortunately, little is known about the mechanisms involved in focal amplifications of 1q21 or other amplifications known to occur during tumor progression. We therefore undertook a comprehensive metaphase analysis to study the cytogenetic progression of the JT1q12 aberrations. We investigated 70 patient specimens showing 1q aberrations by G-banding. Metaphase studies utilizing fluorescence in-situ hybridization (FISH) and spectral karyotyping (SKY) techniques revealed duplications of RCs which were cryptic to G-banding. Sixty-nine cases showed 1q21 amplification of CKS1B with a CN of 1q21 ranging from 3–12 per metaphase cell. Twenty patients showed a 1q21 CN of 3, 19 patients showed a CN of 4, 16 patients with a CN of 5, 5 patients with a CN of 6, 6 patients with a CN of 7–8, 2 patients with a CN of 9–11, and 1 patient with a CN of 12. Thirty-five patients showed JT1q12 related deletions in RCs,11 patients with 16q-, 6 patients lost 19q-, 3 patients lost 6q-, and 2 patients each with 5q- and 8p-. Five patients showed focal amplifications of the 1q12∼23 amplicon by a breakage-fusion-bridge (BFB) cycle mechanism. The resulting focal amplifications were inverted duplications of extended ladder-like structures with 2–8 copies of the 1q12∼23 amplicon. These cases showed site specific breakage in the 1q12 pericentromeric heterochromatin, which mediated the organization of the amplicon by bracketing both the proximal and distal ends of the amplicon. One case of particular interest demonstrated BFB cycles incorporating alternating segments of chromosome 16q11 and the 1q12∼23 amplicon, demonstrating the simultaneous amplification of segments of two non-homologous chromosomes. The amplified segments of both chromosomes 1q12∼23 and 16 then translocated together to multiple RCs, resulting in arm-length deletions in RCs. The unexpected novel finding in this study was the juxtaposition of JT1q12 pericentromeric heterochromatin with the distal segment of a RC resulting in the focal amplification of the adjacent RC segment. In 4 patients the distal duplicated segment of the RC and the adjacent JT1q12 subsequently translocated to new RCs, thus resulting in the simultaneous duplication of chromosome segments both proximal and distal to the 1q12 pericentromeric heterochromatin. Three of these focal duplications involved the distal 8q, including the locus of MYC, and one involved the distal 18q, including the locus of BCL2. This newly identified type of focal amplification provides evidence that 1q12 pericentromeric instability can also provide a mechanism for the amplification of chromosome segments on RCs and thereby simultaneously increase the CN of genes thought to play a role in the progression of MM, including MYC, BCL2, and the 1q12∼23 amplicon.
Disclosures:
Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.
Exploiting the ZIP4 homologue within the wheat Ph1 locus has identified two lines exhibiting homoeologous crossover in wheat-wild relative hybrids