The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
Bibliographical noteFunding Information:
We thank the members of the Broad Institute Genome Sequencing Platform for their part in this work. This study was supported by the US National Human Genome Research Institute (NHGRI) Large Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the Kohlberg Foundation (L.A.G.), the Starr Cancer Consortium (M.A.R., F.D., A.T., G.G., and L.A.G.), the Prostate Cancer Foundation (M.A.R.), US Department of Defense Synergy Awards (PC101020 to F.D., L.A.G., and M.A.R.) and a New Investigator Award (PC094516 to F.D.), the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (US National Institutes of Health [NIH] P50 CA090381), the US National Cancer Institute, Early Detection Research Network (U01CA111275 and NCI EDRN to F.D. and M.A.R.), the US National Cancer Institute (R01 CA125612 to F.D. and M.A.R.), the Fondazione Trentina per la Ricerca sui Tumori (F.D.), the Swiss Science Foundation (PASMP3_134379/1 to J.-P.T.), the National Institute of General Medical Sciences ( T32GM007753 to S.C.B.), and a US NIH Director’s New Innovator Award (DP2OD002750 to L.A.G.). L.A.G. is an equity holder and consultant in Foundation Medicine, a consultant to Novartis and Millenium/Takeda, and a recipient of a grant from Novartis.