Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination.
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.
NantOmics LLC, Santa Cruz, CA 95060;
J Zachary
JZ
Sanborn
Samsung Advanced Institute of Technology, Suwon-si, Gyeonggi-do, 443-803, Korea;
Jongsuk
J
Chung
Department of Statistics, University of California, Berkeley, CA 94720-3860;
Elizabeth
E
Purdom
Department of Biomedical Engineering, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97239;
Nicholas J
NJ
Wang
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia;
Hojabr
H
Kakavand
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia;
James S
JS
Wilmott
Department of Medical and Molecular Genetics, Oregon Health & Science University, Portland, OR 97239-30;
Timothy
T
Butler
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia; Royal Prince Alfred Hospital, The University of Sydney, Camperdown, NSW 2050, Australia;
John F
JF
Thompson
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia;
Graham J
GJ
Mann
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia;
Lauren E
LE
Haydu
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia; Royal Prince Alfred Hospital, The University of Sydney, Camperdown, NSW 2050, Australia;
Robyn P M
RP
Saw
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Klaus J
KJ
Busam
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
Roger S
RS
Lo
Department of Hematology and Oncology, University of California, San Francisco, CA 94143-1770;
Eric A
EA
Collisson
Samsung Electronics, Inc. Seocho-gu, Seoul 137-857, Korea;
Joe S
JS
Hur
Department of Medical and Molecular Genetics, Oregon Health & Science University, Portland, OR 97239-30;
Paul T
PT
Spellman
Department of Dermatology, University of California, San Francisco, CA 94115; chorj@derm.ucsf.edu JCleaver@cc.ucsf.edu Boris.Bastian@ucsf.edu.
James E
JE
Cleaver
Department of Biomedical Engineering, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97239;
Joe W
JW
Gray
Samsung Advanced Institute of Technology, Suwon-si, Gyeonggi-do, 443-803, Korea;
Nam
N
Huh
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Rajmohan
R
Murali
Melanoma Institute Australia, Crows Nest, NSW 1585, Australia; Royal Prince Alfred Hospital, The University of Sydney, Camperdown, NSW 2050, Australia;
Richard A
RA
Scolyer
Department of Pathology, University of California, San Francisco, CA 94143-0511 chorj@derm.ucsf.edu JCleaver@cc.ucsf.edu Boris.Bastian@ucsf.edu.
Boris C
BC
Bastian
Department of Dermatology, University of California, San Francisco, CA 94115; chorj@derm.ucsf.edu JCleaver@cc.ucsf.edu Boris.Bastian@ucsf.edu.
Raymond J
RJ
Cho
D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D009362:Neoplasm Metastasis; D010802:Phylogeny
genetics; melanoma; metastasis