Early and multiple origins of metastatic lineages within primary tumors

Autor(es)

Zhao, Zi-Ming ^[1] ; Zhao, Bixiao ^[2] ; Bai, Yalai ^[3] ; Iamarino, Atila ^[1] ; Gaffney, Stephen G. ^[1] ; Schlessinger, Joseph ^[4] ; Lifton, Richard P. ^[2] ; Rimm, David L. ^[3] ; Townsend, Jeffrey P. ^{[5, 1, 6]}

Afiliação do(s) autor(es)

^[1] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT 06510 - USA

^[2] Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06520 - USA

^[3] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06520 - USA

^[4] Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 - USA

^[5] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 - USA

^[6] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06511 - USA

• Tipo de documento: Artigo Científico
• Fonte: Proceedings of the National Academy of Sciences of the United States of America; v. 113, n. 8, p. 2140-2145, FEB 23 2016.
• Citações Web of Science: 45

Resumo

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. (AU)

• Processo FAPESP: 13/15144-8 - Evolução genômica de grandes vírus de DNA de insetos
• Beneficiário: Atila Iamarino
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 12/04818-5 - Evolução e filodinâmica dos recombinantes BF de HIV-1 da América do Sul
• Beneficiário: Atila Iamarino
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado