Chiu Connie G, Nakamura Yoshitaka, Chong Kelly K, Huang Sharon K, Kawas Neal P, Triche Timothy, Elashoff David, Kiyohara Eiji, Irie Reiko F, Morton Donald L, Hoon Dave S B
Department of Molecular Oncology and Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA;
Department of Molecular Oncology and.
Clin Chem. 2014 Jun;60(6):873-85. doi: 10.1373/clinchem.2013.213611. Epub 2014 Apr 9.
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.
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.
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.
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.
在转移性黑色素瘤患者中已发现循环肿瘤细胞（CTC），其与黑色素瘤晚期及患者预后不良相关。我们推测CTC携带着对远处系统性转移发展至关重要的基因组改变。在此，我们展示了首个基于全基因组拷贝数变异（CNA）和杂合性缺失（LOH）的黑色素瘤CTC特征。
使用抗黑色素瘤相关细胞表面神经节苷脂的抗体，从13例处于区域转移IIIB/C期的黑色素瘤患者的外周血单核细胞中分离出CTC。
我们对CTC中的251个CNA进行了特征分析。比较分析表明，配对的CTC与肿瘤转移灶之间的单核苷酸多态性图谱一致性>90%。特别是，患者之间存在显著的复发性CNA。在探索性研究中，在27例患者的远处转移（IV期）中验证了几种最常见的与CTC相关的CNA的存在，这表明某些基因组改变从区域转移传播至CTC并进而传播至远处系统性转移。最后，一个由5个与CTC相关的CNA [CSMD2（CUB和寿司多结构域2），1p35.1；CNTNAP5（接触蛋白相关蛋白样5），2q14.3；NRDE2（RNA干扰所需的NRDE - 2，含结构域），14q32.11；ADAM6（ADAM金属蛋白酶结构域6，假基因），14q32.33；以及TRPM2（瞬时受体电位阳离子通道，M亚家族，成员2），21q22.3]组成的探索性生物标志物组，对35例IIIB/C期黑色素瘤患者的黑色素瘤复发[风险比（HR），1.14；置信区间（CI），1.00 - 1.44；P = 0.0471]和死亡（HR，2.86；CI，1.23 - 14.42；P = 0.0014）具有预后评估作用，由生物标志物组定义的高风险组和低风险组的5年无病生存率分别为13%对69%（P = 0.0006），总生存率分别为28%对94%。
本研究提供了首个基于CNA的详细黑色素瘤CTC图谱，并说明了如何将CTC用作识别系统性转移的新方法。
