Interdependent genomic restructuring, or “chromoplexy,” drives prostate cancer progression.

  • Major finding: Interdependent genomic restructuring, or “chromoplexy,” drives prostate cancer progression.

  • Approach: Somatic alterations and clonal tumor progression were characterized by whole-genome sequencing.

  • Impact: Prostate cancer evolution may be punctuated by successive genomic derangement events.

Exome sequencing of human prostate cancer samples has characterized recurrent oncogenic mutations and chromosomal deletions that are critical for tumor initiation and progression. In addition, structural genomic rearrangements, such as ETS gene fusions, commonly occur in prostate adenocarcinomas and contribute to tumor progression, but how these chromosomal rearrangements accumulate during prostate carcinogenesis is unclear. To profile the genome-wide spectrum of somatic alterations in prostate cancer, Baca and colleagues performed whole-genome sequencing and DNA copy number profiling of 57 prostate tumors and matched normal tissues. This analysis identified complex chains of DNA rearrangements accompanied by significant DNA deletions that spanned breakpoints from distinct fusions. Computational modeling of this chromosomal rearrangement signature indicated that these events occurred in an interdependent process, referred to as “chromoplexy,” which was detected in the majority of prostate cancers and frequently involved concurrent fusions between several distant chromosomal regions. In particular, chromoplexy was prevalent in highly expressed genomic regions of ETS fusion–positive prostate tumors and induced coordinated dysregulation of multiple cancer genes, including deletion of tumor suppressors and generation of oncogenic ETS fusions, suggesting that this process imparts a selective growth advantage that promotes prostate carcinogenesis. Analysis of common genomic deletions in relation to germline single-nucleotide polymorphisms classified these alterations as clonal or subclonal events in tumorigenesis and uncovered a consensus path of prostate cancer evolution consisting of sequential disruption of specific genes. Furthermore, a subset of chromoplexy-associated rearrangement chains was uniquely subclonal, suggesting that additional rounds of chromoplexy may drive prostate cancer progression. Although the mechanisms underlying this process are yet to be determined, these results support a continuum model of prostate cancer evolution in which several successive, punctuated chromoplexy events induce the accumulation of widespread structural rearrangements.

Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666–77.

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