LeafRank: A phylodynamic framework for inferring relative fitness from single-cell phylogenies in chromosomally unstable tumors.

Tumors contain cancer cells with diverse growth potentials that shape evolutionary trajectories, yet this fitness diversity remains difficult to quantify in cases of whole-genome duplication (WGD) and chromosomal instability. We present LeafRank, a mathematical framework that leverages single-cell DNA-seq phylogenies to infer the relative fitness of individual cells. Using a multi-type branching process model, LeafRank integrates full tree topology, including branch lengths and bifurcation patterns, to estimate marginal fitness probabilities under punctuated evolutionary regimes driven by rare driver events. To account for elevated aberration rates following WGD, we introduce a tree-rescaling strategy that adjusts for lineage-specific genomic instability. Unlike methods focused on predefined subclones, LeafRank ranks all sampled cells, enabling flexible assessment of growth heterogeneity. Simulations demonstrate high accuracy across spatial and non-spatial virtual tumors. Applied to ovarian cancer, LeafRank reveals directional and parallel selection in WGD tumors and identifies recurrent copy number events enriched in high-fitness lineages. WGD lineages do not show immediate growth advantages but acquire fitness through subsequent alterations.