title: Early and multiple origins of metastatic lineages within primary tumors.
abstract: Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.
authors: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510; Jeffrey.Townsend@Yale.edu Joseph.Schlessinger@Yale.edu Zi-ming.Zhao@Yale.edu.
authors: Zi-Ming
authors: ZM
authors: Zhao
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06520;
authors: Bixiao
authors: B
authors: Zhao
authors: Department of Pathology, Yale School of Medicine, New Haven, CT 06520;
authors: Yalai
authors: Y
authors: Bai
authors: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510;
authors: Atila
authors: A
authors: Iamarino
authors: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510;
authors: Stephen G
authors: SG
authors: Gaffney
authors: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Jeffrey.Townsend@Yale.edu Joseph.Schlessinger@Yale.edu Zi-ming.Zhao@Yale.edu.
authors: Joseph
authors: J
authors: Schlessinger
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06520;
authors: Richard P
authors: RP
authors: Lifton
authors: Department of Pathology, Yale School of Medicine, New Haven, CT 06520;
authors: David L
authors: DL
authors: Rimm
authors: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06520; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511 Jeffrey.Townsend@Yale.edu Joseph.Schlessinger@Yale.edu Zi-ming.Zhao@Yale.edu.
authors: Jeffrey P
authors: JP
authors: Townsend
mesh_terms: D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009857:Oncogenes; D010802:Phylogeny; D013997:Time Factors
keywords: ancestral reconstruction; cancer; chronograms; oncogenes; tumor phylogenetics