Fig. 8: Chromosomal instability creates copy-number heterogeneity prior to copy-number complexity.

A Successive BFB cycles can generate progressive DNA losses at the broken ends of chromosomes resulting in a gradual attenuation (sloping) of DNA copy number towards either telomeric (top) or centromeric (bottom) boundaries. Individual broken ends in single cells may acquire terminal duplications that become visible after clonal expansion, but the population average will accrue DNA loss due to deficient DNA replication. B Sloping DNA copy number on Chrs.9, 11, and 12 (black dots) in the HGD sample from patient 10. The constant DNA copy number of the other homolog is shown in gray. In the regions of sloping copy-number variation on Chrs.9 and 11 in HGD, we observe clonal copy-number changepoints in IMEAC, suggesting clonal expansion of a subclone/single cell in the HGD sample. C Copy-number evolution revealed in longitudinal BE sequencing data published by Killcoyne et al. (2020)⁵⁵. In this patient (patient 86), the NDBE sample in the first biopsy (0 month) displays sloping (1p terminus) and subclonal (1q terminus) copy-number variation. A subsequent biopsy with HGD (at 60 months) from the same patient shows a (sub)clonal paracentric loss on 1p with regional copy-number oscillation near the telomeric boundary; another NDBE lesion (timing unspecified) shows chromothripsis at the 1q-terminus in the same region of subclonal copy-number gain in the NDBE lesion at 0 month. Both examples indicate copy-number heterogeneity in the ancestral NDBE lesion. See Supplementary Fig. 11 for additional examples.