Characteristic sequence motifs located at the genomic breakpoints of the translocation t(X;18) in synovial sarcomas

Abstract

The SYT-SSXI and SYT-SSX2 fusion genes, derived by reciprocal translocations t(X;18), are acquired genetic events strongly associated with the tumorigenesis of synovial sarcoma. In approaching the mechanisms underlying the formation of these fusion oncogenes, we have analysed the genomic sequences surrounding the SYT-SSX breakpoints in 10 tumors, two expressing SYT-SSXI and eight expressing SYT-SSX2 fusion transcripts. The breakpoints were found to be clustered in the 5 0 end of intron 10 of SYT, and in two cluster regions within intron 4 of SSX2, whereas the two breakpoints in SSX1 intron 4 were 0.5 kb apart. SYT intron 10 is abundant in repetitive regions with the interspersed repeats occupying 66% of the whole intron. Nine of the 10 breakpoints in intron 10 of SYT and six of the eight breakpoints in intron 4 of SSX2 were at or near repetitive regions. These findings suggest that repetitive regions may contribute to the distribution of genomic breakpoints. Several of the fusion sequences exhibited characteristic signs of nonhomologous end joining, including microhomologies at the end points as well as deletions. Sequences highly homologous (83-94%) to consensus topoisomerase II cleavage sites were identified at or near the breakpoints in all 10 tumors, suggesting a role of this enzyme in creating staggered ends at the breakpoint. Furthermore, sequences highly homologous to consensus Translin binding sequences were found at the breakpoints in two cases, and an Alu-Alu fusion and an insertion of a 206-bp LINE-1 element were found at the breakpoint in one case each. The demonstration of characteristic sequences at the SYT-SSX breakpoint regions is expected to improve our understanding of the molecular genetic mechanisms behind translocations in general, and of the SYT-SSX fusions in synovial sarcoma in particular.

Sequencing human–gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites

“…6), one possibility may be a microhomology-mediated end-joining (MMEJ) mechanism, recently reported as a nonclassical NHEJ mechanism for translocations in mammals (Yan et al 2007). Sequence microhomology and site-specific recombinogenic sequences in the vicinity of the breakpoints have been associated with translocations in evolutionary rearrangements and cancer (Kehrer-Sawatzki et al 2002;Abeysinghe et al 2003;Wei et al 2003). We identified sequence motifs (e.g., topoisomerase II and translin sites) consistent with DSB and repair mechanisms generating overhangs at several human-NLE gibbon breakpoints (Negrini et al 1993;Kanoe et al 1999;Wei et al 2003).…”

“…Sequence microhomology and site-specific recombinogenic sequences in the vicinity of the breakpoints have been associated with translocations in evolutionary rearrangements and cancer (Kehrer-Sawatzki et al 2002;Abeysinghe et al 2003;Wei et al 2003). We identified sequence motifs (e.g., topoisomerase II and translin sites) consistent with DSB and repair mechanisms generating overhangs at several human-NLE gibbon breakpoints (Negrini et al 1993;Kanoe et al 1999;Wei et al 2003). We propose that these overhangs may have been repaired by an ''error-prone'' mechanism, creating some of the smaller breakpoint intervals (Fig.…”

Molecular characterisation of the t(1;15)(p22;q22) translocation in the prostate cancer cell line LNCaP

“…Indeed, deletions and loss of heterozygosity (LOH) of 1p and 15q22 have been reported in prostate cancer (Chu et al, 2003;Dumur et al, 2003). Deletion flanking translocation breakpoints have been previously observed in solid tumours (Kanoe et al, 1999;Wei et al, 2003). In this study, two genes, PSTPIP1 and RCN2 have been deleted in the der(15) chromosome, corresponding to the low expression levels of these genes.…”

SSX2 (synovial sarcoma, X breakpoint 2)

“…This region lacks the KRAB repressive domain but retains the SSXRD region (Crew et al, 1995;de Leeuw et al, 1995;Wei et al, 2003). SS presents in two distinct morphologies, monophasic, populated by spindle tumor cells, and biphasic with an additional glandular epithelial component.…”