Cell depth and the role of replication rate heterogeneity in relapse. (A) As cells replicate they accumulate random microsatellite (MS) alterations which create a unique genetic identifiers. The genetic distance of each cell from the root is defined as cell depth. The accumulation of MS mutations can be translated to the number of replications (deduced from MS mutation rate). Therefore, deep cells, namely cells that are far away from the root, had undergone more replications and the opposite is true for shallow cells (adapted from Wasserstrom et al¹⁴ ). (B) Relapse is initiated by cells that escape chemotherapy stochastically. Cancer cells at relapse are descendants of these cells at diagnosis. Y-axis represents depth in arbitrary units. (C) Relapse is initiated by quiescent cells unharmed by chemotherapy. The cells that initiated relapse are shallow because they divided rarely before relapse. Cells at relapse are descendants of these cells.