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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2140 - 2145 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
23.02.2016
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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. The knowledge that cancer is an evolutionary process is old, but only recently can sequencing technology provide data for clinically relevant evolutionary analyses of cancer. Approaches developed for evolutionary biology can reveal the relationship among clonal lineages, the ancestral states of gene sequences, and the timing of evolutionary events. We performed whole exome sequencing of cancer tissues from multiple sites of dozens of subjects, demonstrating nonlinear patterns of tumor progression and early origins of metastatic lineages and quantifying the times of occurrence of driver mutations. These findings direct research attention away from the search for genes that induce metastasis toward genes that are mutated early in tumorigenesis, providing therapeutic targets effective against both primary tumors and metastases. 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. |
| Author | Zhao, Bixiao Zhao, Zi-Ming Bai, Yalai Schlessinger, Joseph Townsend, Jeffrey P. Gaffney, Stephen G. Iamarino, Atila Lifton, Richard P. Rimm, David L. |
| Author_xml | – sequence: 1 givenname: Zi-Ming surname: Zhao fullname: Zhao, Zi-Ming organization: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510 – sequence: 2 givenname: Bixiao surname: Zhao fullname: Zhao, Bixiao organization: Department of Genetics, Yale School of Medicine, New Haven, CT 06520 – sequence: 3 givenname: Yalai surname: Bai fullname: Bai, Yalai organization: Department of Pathology, Yale School of Medicine, New Haven, CT 06520 – sequence: 4 givenname: Atila surname: Iamarino fullname: Iamarino, Atila organization: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510 – sequence: 5 givenname: Stephen G. surname: Gaffney fullname: Gaffney, Stephen G. organization: Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510 – sequence: 6 givenname: Joseph surname: Schlessinger fullname: Schlessinger, Joseph organization: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520 – sequence: 7 givenname: Richard P. surname: Lifton fullname: Lifton, Richard P. organization: Department of Genetics, Yale School of Medicine, New Haven, CT 06520 – sequence: 8 givenname: David L. surname: Rimm fullname: Rimm, David L. organization: Department of Pathology, Yale School of Medicine, New Haven, CT 06520 – sequence: 9 givenname: Jeffrey P. surname: Townsend fullname: Townsend, Jeffrey P. organization: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26858460$$D View this record in MEDLINE/PubMed |
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| Notes | 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. |
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| Title | Early and multiple origins of metastatic lineages within primary tumors |
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