Details

Autor(en) / Beteiligte

• Zhao, Zi-Ming
• Zhao, Bixiao
• Bai, Yalai
• Iamarino, Atila
• Gaffney, Stephen G.
• Schlessinger, Joseph
• Lifton, Richard P.
• Rimm, David L.
• Townsend, Jeffrey P.

Titel

Early and multiple origins of metastatic lineages within primary tumors

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2016-02, Vol.113 (8), p.2140-2145

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.