Genome-wide characterization of circulating tumor cells identifies novel prognostic genomic alterations in systemic melanoma metastasis.
BACKGROUND
Circulating tumor cells (CTC) have been found in patients with metastatic melanoma and are associated with advanced melanoma stage and poor patient outcome. We hypothesize that CTC harbor genomic changes critical in the development of distant systemic metastasis. Here, we present the first genome-wide copy-number aberration (CNA) and loss of heterozygosity (LOH)-based characterization of melanoma CTC.


METHODS
CTC were isolated from peripheral blood monocytes of 13 melanoma patients with regional metastasis stage IIIB/C using antibodies against melanoma-associated cell surface gangliosides.


RESULTS
We characterized 251 CNA in CTC. Comparative analysis demonstrated >90% concordance in single-nucleotide polymorphism profiles between paired CTC and tumor metastases. In particular, there were notable recurring CNA across patients. In exploratory studies, the presence of several top CTC-associated CNA was verified in distant metastasis (stage IV) from 27 patients, suggesting that certain genomic changes are propagated from regional metastasis to CTC and to distant systemic metastases. Lastly, an exploratory biomarker panel derived from 5 CTC-associated CNA [CSMD2 (CUB and Sushi multiple domains 2), 1p35.1; CNTNAP5 (contactin associated protein-like 5), 2q14.3; NRDE2 (NRDE-2, necessary for RNA interference, domain containing), 14q32.11; ADAM6 (ADAM metallopeptidase domain 6, pseudogene), 14q32.33; and TRPM2 (transient receptor potential cation channel, subfamily m, member 2), 21q22.3] conferred prognostic utility for melanoma recurrence [hazard ratio (HR), 1.14; CI, 1.00-1.44; P = 0.0471] and death (HR, 2.86; CI, 1.23-14.42; P = 0.0014) in 35 patients with stage IIIB/C melanoma, with a 5-year disease-free survival of 13% vs 69% (P = 0.0006) and overall survival of 28% vs 94% between high-risk and low-risk groups defined by the biomarker panel, respectively.


CONCLUSIONS
This study provides the first detailed CNA-based profile of melanoma CTC and illustrates how CTC may be used as a novel approach for identification of systemic metastasis.
Department of Molecular Oncology and Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA;
Connie G
CG
Chiu
Department of Molecular Oncology and.
Yoshitaka
Y
Nakamura
Department of Molecular Oncology and.
Kelly K
KK
Chong
Department of Molecular Oncology and.
Sharon K
SK
Huang
Department of Molecular Oncology and.
Neal P
NP
Kawas
Center for Personalized Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA;
Timothy
T
Triche
Department of Medicine Statistics Core, UCLA School of Medicine, Los Angeles, CA;
David
D
Elashoff
Department of Molecular Oncology and.
Eiji
E
Kiyohara
Department of Biotechnology, John Wayne Cancer Institute, Santa Monica, CA.
Reiko F
RF
Irie
Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA;
Donald L
DL
Morton
Department of Molecular Oncology and hoon@jwci.org.
Dave S B
DS
Hoon
D055106:Genome-Wide Association Study; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000556:secondary*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis