Poly‐gene fusion transcripts and chromothripsis in prostate cancer

Chunxiao Wu, Alexander W. Wyatt, Andrew McPherson, Dong Lin, Brian J. McConeghy, Fan Mo, Robert Shukin, Anna V. Lapuk, Steven J. M. Jones, Yongjun Zhao, Marco A. Marra, Martin E. Gleave, Stanislav V. Volik, Yuzhuo Wang, S. Cenk Sahinalp, Colin C. Collins

Complex genome rearrangements are frequently observed in cancer but their impact on tumor molecular biology is largely unknown. Recent studies have identified a new phenomenon involving the simultaneous generation of tens to hundreds of genomic rearrangements, called chromothripsis. To understand the molecular consequences of these events, we sequenced the genomes and transcriptomes of two prostate tumors exhibiting evidence of chromothripsis. We identified several complex fusion transcripts, each containing sequence from three different genes, originating from different parts of the genome. One such poly-gene fusion transcript appeared to be expressed from a chain of small genomic fragments. Furthermore, we detected poly-gene fusion transcripts in the prostate cancer cell line LNCaP, suggesting they may represent a common phenomenon. Finally in one tumor with chromothripsis, we identified multiple mutations in the p53 signaling pathway, expanding on recent work associating aberrant DNA damage response mechanisms with chromothripsis. Overall, our data show that chromothripsis can manifest as massively rearranged transcriptomes. The implication that multigenic changes can give rise to poly-gene fusion transcripts is potentially of great significance to cancer genetics.