Elements and evolutionary determinants of genomic divergence between paired primary and metastatic tumors
Fig 2
Elements of Metastatic-Primary genomic divergence and their potential pattern in tumor evolution.
(A) A sample tree (schematic) based on somatic variant analysis of paired Metastatic (M) and Primary (P) tumor samples depicts the two branches involving the number of metastatic specific (Bm, dashed green line) and primary specific somatic variants (Bp, dashed blue line), respectively. We focus primarily on the variants accumulated in the metastatic seeding cell (green circle) before its dissemination (Bmd), as it is directly related to the primary tumor growth and the genetic determinants of metastatic dissemination. Below the sample tree shown a genealogy tree focusing on the lineage of the seeding cell, where we note the branches that represent Bmd and Bp, respectively. Detectable ancestors in the primary at a frequency of γ (DAγ) and the most recent detectable ancestor at α and γ (MRDAα and MRDAγ) of the seeding cell are also indicated, respectively. Here γ is the variant allele frequency threshold above which substantial presence of a variant may be deemed; α is the frequency threshold of sequencing detectability. (B) If a cell with k variants “cancels” its dissemination (i.e., stays in the primary tumor) and its progeny cell with k + 1 variants migrates instead, the resulting Bmd can drop if the progenitor cell with k variants eventually grows into a detectable subclone in the primary tumor. In this case, it becomes the most recent detectable ancestor of the seeding cell. More generally, Bmd can decrease if an ancestor along the genealogy the the seeding cell becomes detectable due to subclone expansion. (C) We hypothesize that Bmd and Bp are affected by the kinetics of primary tumor growth. Under the growth pattern of progressive subclonal divergence, late seeding would lead to larger Bmd than early seeding as only the early subclones are detectable; Bp stays constant as the detectable portion of the seeding cell lineage is restricted. By contrast, detectable subclones can appear late leading to the pattern of sub-clonal convergence (due to selection or other ecological forces), under which scenario seeding from early or late detectable subclones may lead to similar Bmd, but differs in Bp.