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Clonal evolution can be reconstructed from estimates of the relative abundance frequency of subclone-specific alterations in tumor biopsies, which, in turn, inform on its composition. However, estimating these frequencies is complicated by the high genetic instability that characterizes many cancers. Models for genetic instability suggest that copy number alterations CNAs can influence mutation-frequency estimates and thus impede efforts to reconstruct tumor phylogenies.

Our analysis suggested that accurate mutation frequency estimates require accounting for CNAs—a challenging endeavour using the genetic profile of a single tumor biopsy. Pan-cancer tumor profiling has identified recurrent alterations that are associated with tumor etiology at the loci of thousands of genes but the interpretation of genetic alterations remains a major challenge 1 , 2 , 3.

Knowledge about the clonal evolution of tumors can point to genetic alterations that both contribute to tumorigenesis, indicate prognostically relevant intratumoral variability, and point to refractory tumor subclones 4 , 5. Specifically, clonal evolution—depicted as a phylogenetic tree in Fig. Consequently, tumor-subclone characterization is essential for designing personalized therapies that target all tumor subclones and may hold the key to predicting tumor progression, metastases, drug sensitivity, and patient outcome.