a, Diagram of ‘closed chain’ pattern of chromosomal breakage and rejoining. Breaks are induced in a set of loci (left), followed by an exchange of free ends without loss of chromosomal material (middle), leading to the observed pattern of balanced (copy neutral) translocations involving a closed set of breakpoints (right). b, Complex rearrangement in prostate tumour PR-1701. TMPRSS2– ERG is produced by a closed quartet of balanced rearrangements involving 4 loci on chromosomes 1 and 21. Top, each rearrangement is supported by the presence of discordant read pairs in the tumour genome but not the normal genome (coloured bars connected by blue lines). Thin bars represent sequence reads; directionality represents mapping orientation on the reference genome. Figures are based on the Integrative Genomics Viewer ( http://www.broadinstitute.org/igv). Bottom, Diagram of breakpoints and balanced translocations. Hatching indicates sequences that are duplicated in the derived chromosomes at the resulting fusion junctions. c, Complex rearrangement in prostate tumour PR-2832 involving breakpoints and fusions at 9 distinct genomic loci. Hatching indicates sequences that are duplicated or deleted in the derived chromosomes at the resulting fusion junctions. For breakpoints in intergenic regions, the nearest gene in each direction is shown. In addition to the sheer number of regions involved, this complex rearrangement is notable for the abundance of breakpoints in or near cancer-related genes, such as TBK1, MAP2K4, TP53 and ABL1.