Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

J. Zachary Sanborn, Jongsuk Chung, Elizabeth Purdom, Nicholas J. Wang, Hojabr Kakavand, James S. Wilmott, Timothy Butler, John F. Thompson, Graham J. Mann, Lauren E. Haydu, Robyn P M Saw, Klaus J. Busam, Roger S. Lo, Eric A. Collisson, Joe S. Hur, Paul Spellman, James E. Cleaver, Joe Gray, Nam Huh, Rajmohan MuraliRichard A. Scolyer, Boris C. Bastian, Raymond J. Cho

Research output: Contribution to journalArticle

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Abstract

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.

Original languageEnglish (US)
Pages (from-to)10995-11000
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number35
DOIs
StatePublished - Sep 1 2015

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Melanoma
Neoplasm Metastasis
Neoplasms
Virus Integration
Exome
Mouse mammary tumor virus
Population
Theoretical Models
Mutation
Therapeutics

Keywords

  • Genetics
  • Melanoma
  • Metastasis

ASJC Scopus subject areas

  • General

Cite this

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination. / Sanborn, J. Zachary; Chung, Jongsuk; Purdom, Elizabeth; Wang, Nicholas J.; Kakavand, Hojabr; Wilmott, James S.; Butler, Timothy; Thompson, John F.; Mann, Graham J.; Haydu, Lauren E.; Saw, Robyn P M; Busam, Klaus J.; Lo, Roger S.; Collisson, Eric A.; Hur, Joe S.; Spellman, Paul; Cleaver, James E.; Gray, Joe; Huh, Nam; Murali, Rajmohan; Scolyer, Richard A.; Bastian, Boris C.; Cho, Raymond J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 35, 01.09.2015, p. 10995-11000.

Research output: Contribution to journalArticle

Sanborn, JZ, Chung, J, Purdom, E, Wang, NJ, Kakavand, H, Wilmott, JS, Butler, T, Thompson, JF, Mann, GJ, Haydu, LE, Saw, RPM, Busam, KJ, Lo, RS, Collisson, EA, Hur, JS, Spellman, P, Cleaver, JE, Gray, J, Huh, N, Murali, R, Scolyer, RA, Bastian, BC & Cho, RJ 2015, 'Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 35, pp. 10995-11000. https://doi.org/10.1073/pnas.1508074112
Sanborn, J. Zachary ; Chung, Jongsuk ; Purdom, Elizabeth ; Wang, Nicholas J. ; Kakavand, Hojabr ; Wilmott, James S. ; Butler, Timothy ; Thompson, John F. ; Mann, Graham J. ; Haydu, Lauren E. ; Saw, Robyn P M ; Busam, Klaus J. ; Lo, Roger S. ; Collisson, Eric A. ; Hur, Joe S. ; Spellman, Paul ; Cleaver, James E. ; Gray, Joe ; Huh, Nam ; Murali, Rajmohan ; Scolyer, Richard A. ; Bastian, Boris C. ; Cho, Raymond J. / Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 35. pp. 10995-11000.
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abstract = "Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.",
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AU - Chung, Jongsuk

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AU - Wang, Nicholas J.

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AU - Wilmott, James S.

AU - Butler, Timothy

AU - Thompson, John F.

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AU - Haydu, Lauren E.

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AU - Spellman, Paul

AU - Cleaver, James E.

AU - Gray, Joe

AU - Huh, Nam

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AU - Cho, Raymond J.

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