Figure 2. Evolutionary Bottlenecking and Restriction of Diversity between primary and metastases.

(A) Transient restriction of diversity through an evolutionary bottlenecking process, eg during clonal selection through therapy or during metastatic progression may lead to the requirement for alternative mechanisms to generate ITH. One such mechanism can be generated through structural and whole chromosomal instability (CIN). Tetraploidy is thought to be a precursor of chromosomal instability. (B/C) Multi-region analysis of a primary renal cell carcinoma and its metastatic sites revealed the metastatic lesions were most similar to Region 4 of the primary (adapted from Gerlinger et al 2012). Ploidy analysis revealed that the primary regions were all diploid with the exception of region 4 which was tetraploid. Metastatic sites were sub-tetraploid. (D) Allelic imbalance analysis revealed substantial heterogeneity in chromosome structure between two biopsies of the same metastatic site (M2a and M2b). Taken together with ploidy analysis, these data indicate the possible emergence of CIN at metastatic sites. Longitudinal studies will reveal to what extent metastatic sites represent outgrowth of multiple heterogeneous subclones from the primary tumour and genetic events that may be permissive for metastatic outgrowth during the bottlenecking process. Figure 2 Adapted from references 14 and 18 (Gerlinger et al NEJM 2012 and Gerlinger et al 2010 British Journal of Cancer).