A tandem duplication genotype in high-risk prostate cancer. (A) Copy number profile of hormone-naïve tumor T4, showing focal gains across the entire genome, distinctive of tandem duplications. Key events discussed in the text are annotated. (B) Schematic illustrating how individual tandem duplications present at the genomic level. (C) Serial tandem duplications across the MDM2 loci in T4. The copy number plot shows a focal high gain, with the colored lines representing segments that have been duplicated. Tandem duplication ID is indicated next to each colored line and in brackets is the estimated number of copies of each tandem duplication. For example, the genetic breakpoint of the most focal tandem duplication (green line) was detectable at a high frequency indicating multiple copies, suggesting that the breakpoint itself had been subsequently duplicated, potentially by the broader tandem duplications (pink and blue lines). Note that one breakpoint (purple line) was predicted at <1 suggestive of sub-clonality and highlighting the potential for continual evolution. (D) Transcript expression of MDM2 across the high-risk cohort showing elevated expression in tumor T4 relative to the other tumors and benign samples. (E, F) Chromogenic in situ hybridization of MDM2 in benign tissue (E) and tumor (F) from T4 confirming MDM2 amplification. Note the `clumps’ of staining in the tumor cells suggesting MDM2 amplifications are proximally located (consistent with tandem duplication). (G) Copy number profiles from two tumors in a public dataset, which appear to harbor the distinctive pattern of focal gains across the entire genome (see Additional file 2: Figure S9 for further examples). Oncogenes within focal amplifications are annotated.