Fig. 1.

Illustration of path and oncogenetic tree mutational models inferred from cross-sectional data, and all possible temporal orders of clonal mutations that are consistent with the models. Each arrow between circles represents the acquisition of a new mutation in models inferred from cross-sectional data, and squares represent the accumulation of a new mutation in a clone during the evolution of a tumor. (A) The path model of carcinogenesis implies a linear order of sequential mutations from wild-type through A, B, and C, in order. (B) These are the temporal mutations that a cell lineage, or clone of cells, could acquire during evolution and still be consistent with the cross-sectional path model in A. All other sequences of mutations are inconsistent with the cross-sectional path model (e.g., B, C, AC, and BAC are inconsistent). (C) The oncogenetic tree model of carcinogenesis implies that all tumors begin as wild-type, and can next acquire either mutation A or B. Additionally, C can only occur at any point after mutation A has occurred. (D) All temporal mutations acquired by a clone that are consistent with the cross-sectional oncogenetic tree in C. Note that the order A, B, C is consistent because C occurs after A.