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

• Published in: Oncogene Vol. 22; no. 14; pp. 2215 - 2222
• Main Authors: YONGKUN WEI, MENGHONG SUN, NILSSON, Gunnar, DWIGHT, Trisha, XIE, Yuntao, JIAN WANG, YINGYONG HOU, LARSSON, Olle, LARSSON, Catharina, XIONGZENG ZHU
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 10.04.2003; Nature Publishing Group
• Subjects: Artificial Gene Fusion; Base Sequence; Biological and medical sciences; Breakpoints; Calcium-Binding Proteins; Cancer; Carcinogenesis, carcinogens and anticarcinogens; Chromosomes, Human, Pair 18; Chromosomes, Human, X; Diseases of the osteoarticular system; DNA topoisomerase (ATP-hydrolysing); Foods and miscellaneous; Fusion protein; Genes; Genomics; Humans; Insertion; Medical sciences; Medicin och hälsovetenskap; Membrane Glycoproteins - genetics; Molecular Sequence Data; Neoplasm Proteins - genetics; Nerve Tissue Proteins - genetics; Pathology; Repressor Proteins - genetics; Sarcoma; Sarcoma, Synovial - genetics; Synaptotagmins; Synovial sarcoma; Translocation; Translocation, Genetic; TSN protein; Tumorigenesis; Tumors; Tumors of striated muscle and skeleton; Sweden; Translocation; DNA sequence; Breakpoint; breakpoints; Synovial sarcoma; Genomics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206343

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' 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.