Early and multiple origins of metastatic lineages within primary tumors

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 mole...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2140 - 2145
Main Authors Zhao, Zi-Ming, Zhao, Bixiao, Bai, Yalai, Iamarino, Atila, Gaffney, Stephen G., Schlessinger, Joseph, Lifton, Richard P., Rimm, David L., Townsend, Jeffrey P.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.02.2016
National Acad Sciences
Subjects
Biological Sciences
Cancer
Cell Lineage - genetics
Cell Transformation, Neoplastic - genetics
Evolution, Molecular
Female
Genetic Variation
Humans
Likelihood Functions
Male
Metastasis
Models, Genetic
Mutation
Neoplasm Metastasis - genetics
Neoplasm Metastasis - pathology
Neoplasms - genetics
Neoplasms - pathology
Oncogenes
Phylogenetics
Phylogeny
Time Factors
Tumors
oncogenes
ancestral reconstruction
chronograms
cancer
tumor phylogenetics
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 14
1Z.-M.Z. and B.Z. contributed equally to this work.
Contributed by Joseph Schlessinger, January 5, 2016 (sent for review July 29, 2015; reviewed by Andrew G. Clark and Allen Rodrigo)
Reviewers: A.G.C., Cornell University; and A.R., Australia National University.
Author contributions: J.S., R.P.L., D.L.R., and J.P.T. designed research; Z.-M.Z., B.Z., Y.B., A.I., S.G.G., and J.P.T. performed research; Z.-M.Z., A.I., S.G.G., D.L.R., and J.P.T. contributed new reagents/analytic tools; Z.-M.Z., B.Z., A.I., S.G.G., and J.P.T. analyzed data; and Z.-M.Z., B.Z., Y.B., A.I., S.G.G., J.S., R.P.L., D.L.R., and J.P.T. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1525677113