Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Clin Cancer Res. 2011 Apr 15;17(8):2417-25. doi: 10.1158/1078-0432.CCR-10-2402. Epub 2011 Apr 12.
With the rising incidence of melanoma, more patients are undergoing surveillance for disease recurrence. Our purpose was to study levels of proteins that might be secreted in the blood of patients with metastatic melanoma that can be used for monitoring these individuals.
Genome-wide gene expression data were used to identify abundantly expressed genes in melanoma cells that encode for proteins likely to be present in the blood of cancer patients, based on high expression levels in tumors. ELISA assays were employed to measure proteins in plasma of 216 individuals; 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease split into equal-sized training and test cohorts.
Levels of seven markers, CEACAM (carcinoembryonic antigen-related cell adhesion molecule), ICAM-1 (intercellular adhesion molecule 1), osteopontin, MIA (melanoma inhibitory activity), GDF-15 (growth differentiation factor 15), TIMP-1 (tissue inhibitor of metalloproteinase 1), and S100B, were higher in patients with unresected stage IV disease than in patients with resected stage I/II disease. About 81% of the stage I/II patients in the training set had no marker elevation, whereas 69% of the stage IV patients had elevation of at least one marker (P < 0.0001). Receiver operating characteristic curves for the markers in combination in these two patient populations had an area under curve (AUC) of 0.79 in the training set and 0.8 in the test set. A CART (Classification and Regression Trees) model developed in the training set further improved the AUC in the test set to 0.898.
Plasma markers, particularly when assessed in combination, can be used to monitor patients for disease recurrence and can compliment currently used lactate dehydrogenase and imaging studies; prospective validation is warranted.
随着黑色素瘤发病率的上升，越来越多的患者需要进行疾病复发监测。本研究旨在研究转移性黑色素瘤患者血液中可能存在的、可用于监测这些个体的分泌蛋白的水平。
利用全基因组基因表达数据，根据肿瘤中高表达水平，鉴定黑色素瘤细胞中大量表达的编码蛋白，这些蛋白可能存在于癌症患者的血液中。采用 ELISA 检测 216 例个体（108 例转移性黑色素瘤患者和 108 例年龄和性别匹配的、已切除 I/II 期疾病的患者）的血浆蛋白；将这些患者分为大小相等的训练集和测试集。
CEACAM（癌胚抗原相关细胞黏附分子）、ICAM-1（细胞间黏附分子 1）、骨桥蛋白、MIA（黑色素瘤抑制活性）、GDF-15（生长分化因子 15）、TIMP-1（组织金属蛋白酶抑制剂 1）和 S100B 等 7 种标志物在未切除的 IV 期疾病患者中的水平高于已切除的 I/II 期疾病患者。在训练集中，约 81%的 I/II 期患者无标志物升高，而 69%的 IV 期患者至少有一种标志物升高（P<0.0001）。在这两种患者人群中，标志物联合的受试者工作特征曲线在训练集中的曲线下面积（AUC）为 0.79，在测试集中为 0.8。在训练集中开发的 CART（分类和回归树）模型进一步提高了测试集中的 AUC，达到 0.898。
血浆标志物，特别是联合评估时，可用于监测疾病复发，并可补充目前使用的乳酸脱氢酶和影像学研究；需要进行前瞻性验证。
