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Open Access Publications from the University of California

The genetics of splicing in cancer

  • Author(s): Chen, Justin
  • Advisor(s): Weiss, William A
  • et al.

Alternative splicing plays critical roles in normal development and can promote growth and survival in cancer. Genes that have canonical splice variants that function antagonistically can be ectopically expressed to drive malignant progression. Additionally, aberrant splicing, the production of noncanonical and cancer‐specific mRNA transcripts, can lead to loss‐of‐function in tumor suppressors or activation of oncogenes and cancer pathways. Emerging data suggests that aberrant splicing products and loss of canonically spliced variants correlate with stage and progression in malignancy. Not only do these data illuminate roles for alternative splicing in cancer and intersections between alternative splicing pathways and therapy, but they illustrate the importance of understanding the genetic basis of splicing.

Using a transgenic model of neuroblastoma, we set up a backcrossed genetic system to derive distinct virtual genomes of over 100 individual mice in which we have profiled exon expression in two different neural tissues. We identified splicing quantitative trait loci (sQTL) which map genetic control of splicing and define key splicing motifs. We identify these motifs as sites of recurrent somatic mutations in cancer. We also use this analysis to identify novel effector splicing events. Among these, we show that a triplet splicing event within FUBP1 modulates levels of the MYC oncoprotein in human neuroblastoma‐derived cell line, and correlates with outcome in neuroblastoma.

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