Punctuated Evolution of Prostate Cancer Genomes
Menée sur des échantillons de tissu tumoral et de tissu sain prélevés sur 57 patients atteints d'un cancer de la prostate, cette étude met en évidence un phénomène de "chromoplexie", c'est-à-dire de translocations et de délétions interdépendantes induisant une dérégulation coordonnée de multiples gènes
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. º Interdependent DNA rearrangements may coordinately remodel prostate cancer genomes º Chromoplexy defines a distinct class of complex structural rearrangements º Multiple prostate cancer genes may be dysregulated coordinately º Clonal evolution reveals paths of prostate cancer progression Modeling the genesis of chromosomal rearrangements in prostate cancer genomes reveals that the chromosomal disarray found in a typical tumor may arise via a handful of discrete chromoplexy events during tumor development in which interdependent rearrangements shuffle DNA from five or more chromosomes.