Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination Journal Article
| Authors: | Sanborn, J. Z.; Chung, J.; Purdom, E.; Wang, N. J.; Kakavand, H.; Wilmott, J. S.; Butler, T.; Thompson, J. F.; Mann, G. J.; Haydu, L. E.; Saw, R. P. M.; Busam, K. J.; Lo, R. S.; Collisson, E. A.; Hur, J. S.; Spellman, P. T.; Cleaver, J. E.; Gray, J. W.; Huh, N.; Murali, R.; Scolyer, R. A.; Bastian, B. C.; Cho, R. J. |
| Article Title: | Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination |
| 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. © 2015, National Academy of Sciences. All rights reserved. |
| Keywords: | clinical article; controlled study; human tissue; primary tumor; gene mutation; single nucleotide polymorphism; somatic mutation; genetics; lymph node metastasis; melanoma; metastasis; evolution; cell population; distant metastasis; cell subpopulation; brain metastasis; melanoma cell; chromosome deletion; regional metastasis; skin metastasis; phylogeny; metastatic melanoma; exome; human; priority journal; article |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 112 |
| Issue: | 35 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2015-09-01 |
| Start Page: | 10995 |
| End Page: | 11000 |
| Language: | English |
| DOI: | 10.1073/pnas.1508074112 |
| PROVIDER: | scopus |
| PMCID: | PMC4568214 |
| PUBMED: | 26286987 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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