Characterization Of Complex Chromosomal Aberrations In Prostate Cancer From Whole Genome Sequencing

Prostate cancer is the second most common cause of male cancer deaths in the United States, accounting for 200,000 new cases and 32,000 deaths per year. Chromosomal rearrangements comprise a major mechanism driving prostate carcinogenesis. For example, recurrent gene fusions that render ETS transcription factors under the control of androgen-responsive promoters are present in the majority of prostate cancers. Other types of somatic alterations, such as base substitutions, small insertions/deletions, and chromosomal copy number alterations, have also been described, yet the full repertoire of genomic alterations that underlie primary human prostate cancer remains incompletely characterized. We present here the most comprehensive genome sequencing effort in prostate cancer reported to date. We have characterized the complete genomes of 7 primary prostate cancers and patient-matched normal samples using massively parallel sequencing technology. We observed a mean mutation frequency of 0.9 per megabase, consistent with what has been reported for other tumor types. However, our results indicate that translocations and other chromosomal rearrangements are far more common than expected, with a median of 90 per prostate cancer genome. Several tumors contained chains of balanced rearrangements involving multiple loci associated with known cancer genes. We observed a striking and unexpected relationship between rearrangement breakpoints and chromatin structure, which differed for tumors harboring the ETS gene fusion TMPRSS2-ERG and tumors lacking ETS fusions. We also observed an enrichment of point mutations near rearrangement breakpoints. Three of seven tumors contained rearrangements that disrupted CADM2, a nectin-like member of the immunoglobulin-like cell adhesion molecules; recurrent CADM2 rearrangements were also detected in an independent cohort by fluorescent in situ hybridization (FISH). Four tumors harbored rearrangements disrupting either PTEN, a prostate tumor suppressor, or MAGI2, a PTEN interacting protein not previously implicated in prostate cancer. Together, these results illuminate potential avenues for target discovery and reveal the potential of complex rearrangements to engage prostate tumorigenic mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3925. doi:10.1158/1538-7445.AM2011-3925