Non-confidential abstract
Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer which is prevalent in Southern China, Southeast Asia and North Africa. The development and stepwise progression of NPC involve accumulation of multiple gross genetic changes during the clonal expansion of EBV-infected nasopharyngeal epithelial cell population. Here, using paired-end transcriptome sequencing, we discovered a number of chimeric fusion transcripts in a panel of EBV-positive tumor lines. Among these transcripts, a novel fusion identified from the NPC cell line C666-1 was recurrently detected in 12/144 (8.3%) primary tumors. The fusion gene contains exon 1 of the UBR5 gene on chromosome 8 and exon 7-9 of the ZNF423 gene on chromosome 16 and produces a 94aa chimeric protein including the original C-terminal binding domain of the ZNF423 gene. Notably, the growth of NPC with this rearrangement is dependent on expression of the fusion protein. Knockdown of fusion protein by fusion-specific siRNA significantly inhibited the cell proliferation and colony forming ability in C666-1 cells. The transforming ability of the fusion protein was also confirmed in NIH3T3 fibroblasts. Constitutive expression of this novel gene in NIH3T3 fibroblasts significantly enhanced its anchorage-independent growth in soft agar and induced tumor formation in the nude mice model. These findings suggest that expression of the novel fusion protein might contribute to the transformation of a subset of NPC, possibly by altering the activity of EBFs (early B-cell factors). Identification of this oncogenic fusion protein provides new potential opportunities for therapeutic intervention in NPC.
Advantages
Discovery of novel transforming fusion transcript in 8.3% of NPC. This novel gene may provide new opportunities for therapeutic intervention in NPC