Background
Novel fusion transcripts caused by chromosomal rearrangement are common factors in the development of cancers. We used massively parallel RNA-sequencing to identify new fusion transcripts in colon cancers.
Methods
RNA-seq and TopHat-Fusion were used to identify new fusion transcripts in colon cancers. We then investigated whether the novel fusion transcript NR5A2-KLHL29FT was transcribed from a genomic chromosomal rearrangement. Next, the expression of NR5A2-KLHL29FT was measured by quantitative RT-PCR in colon cancers and matched corresponding normal epithelia.
Results
We identified the fusion transcript NR5A2-KLHL29FT in normal and cancerous epithelia. While investigating this transcript, we unexpectedly found that it was due to an uncharacterized polymorphic germline insertion of NR5A2 sequence from chromosome 1 into the KLHL29 locus at chromosome 2, rather than a chromosomal rearrangement. This germline insertion, which occurred at a population frequency of 0.40, appeared to bear no relationship to cancer development. Moreover, NR5A2-KLHL29FT expression was validated in RNAs from samples with insertions of NR5A2 at the KLHL29 gene locus, but not from samples without this insertion. Notably, NR5A2-KLH29FT expression levels were significantly lower in colon cancers than in matched normal colonic epithelia (p = 0.029), suggesting potential participation of NR5A2-KLHL29FT in the origin or progression of this tumor type.
Conclusions
NR5A2-KLHL29FT was generated from a polymorphism insertion of NR5A2 sequence into the KLHL29 locus. NR5A2-KLHL29FT may influence the origin or progression of colon cancer. Moreover, researchers should be aware that similar fusion transcripts may occur due to trans-chromosomal insertions that are not correctly annotated in genome databases, especially with current assembly algorithms.