Single-cell genetic analysis of 4 patients with hyperdiploidy and translocation demonstrated 2 different patterns of myeloma etiology. (A-D) Hierarchical clustering of genetic information (rows) for each single-cell (columns) established different cell groups or myeloma subclones (left). Cell numbers and subclonal proportions are shown in the bottom. Blue means gains, red means losses, and yellow means positivity for translocation breakpoint. Schematic representations of the most-plausible phylogenetic tree for the defined subclonal populations were depicted (right). (A-B) The earliest ancestral clone that can be detected at the analyzed time point already had both hyperdiploidy and IGH translocations and further evolved by acquiring additional genomic changes. (A) Sample 90/0017, with each derivative chromosomes being lost in different subclones. (B) Sample 12/0366, acquisition of an extra trisomy (HRD11) and a loss of der14. (C-D) Hyperdiploidy preceded IGH translocation as shown in the earliest ancestral clone. (C) Sample 10/133. (D) Sample 11/1096, showing HRD9 as a trisomy acquired independently in 2 subclones. HRD, hyperdiploidy. See supplemental Figure 2 for an additional case study with hyperdiploidy preceding IGH translocation. Evolutionary trees inferred by using the minimum evolution method and genetic distances are provided in supplemental Figure 3.