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Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2140-5. doi: 10.1073/pnas.1525677113. Epub 2016 Feb 8.

Early and multiple origins of metastatic lineages within primary tumors.

Author information

1
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.
2
Department of Genetics, Yale School of Medicine, New Haven, CT 06520;
3
Department of Pathology, Yale School of Medicine, New Haven, CT 06520;
4
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510;
5
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Jeffrey.Townsend@Yale.edu Joseph.Schlessinger@Yale.edu Zi-ming.Zhao@Yale.edu.
6
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.

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.

KEYWORDS:

ancestral reconstruction; cancer; chronograms; oncogenes; tumor phylogenetics

PMID:
26858460
PMCID:
PMC4776530
DOI:
10.1073/pnas.1525677113
[Indexed for MEDLINE]
Free PMC Article

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