4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer
4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer
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DOI：
10.1016/j.molonc.2015.07.004
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发表时间：
2016-01-01
影响因子：
6.6
通讯作者：
Umar, Arzu
中科院分区：
文献类型：
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作者：
De Marchi, Tommaso;Liu, Ning Qing;Umar, Arzu
雌激素受体（ER）阳性肿瘤代表了大多数乳腺恶性肿瘤，并有效地治疗激素疗法，如他莫昔芬。然而，在复发性疾病中，对他莫昔芬治疗的耐药性是常见的，并且是死亡的主要原因。近年来，深入的蛋白质组分析已经能够识别临床上有用的生物标志物，特别是当使用激光捕获显微切割（LCM）减少复杂肿瘤组织的异质性时。在目前的研究中，我们对两组ER阳性乳腺肿瘤患者进行了高分辨率蛋白质组学分析，这些患者在复发时对他莫昔芬治疗表现出良好或不良的结果。从多个医学中心收集了总共112个新鲜冷冻肿瘤，并分为两组：内部训练组和多中心测试组。用LCM富集上皮肿瘤细胞并通过纳米LC Orbitrap质谱法（MS）分析，其在训练集和测试集中分别产生>3000和>4000个定量蛋白质。原始数据可通过ProteomeXchange获得，标识符为PXD 000484和PXD 000485。统计分析显示99种蛋白质的丰度差异，其中4种蛋白质的子集通过多变量逐步下降来选择，以开发他莫昔芬治疗结果的预测因子。4-蛋白特征显著预测测试集中的不良结局患者，与预测性组织病理学特征无关（风险比[HR] = 2.17; 95%置信区间[CI] = 1.15至4.17;多变量考克斯回归p值= 0.017）。提供了一组独立的福尔马林固定石蜡包埋肿瘤组织上PDCD 4（特征蛋白之一）的免疫组织化学（IHC）染色和独立的技术验证（HR = 0.72; 95% CI = 0.57至0.92;多变量考克斯回归p值= 0.009）。我们在此报告了第一个经验证的蛋白质预测他莫昔芬治疗复发性ER阳性乳腺癌的结果。免疫组化进一步显示PDCD 4是一个独立的标志物。(C)2015年，作者。由Elsevier B. V.代表欧洲生物化学学会联合会出版。
Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, we performed high resolution proteomic analysis on two cohorts of ER positive breast tumors derived from patients who either manifested good or poor outcome to tamoxifen treatment upon recurrence. A total of 112 fresh frozen tumors were collected from multiple medical centers and divided into two sets: an in-house training and a multi-center test set. Epithelial tumor cells were enriched with LCM and analyzed by nano-LC Orbitrap mass spectrometry (MS), which yielded >3000 and >4000 quantified proteins in the training and test sets, respectively. Raw data are available via ProteomeXchange with identifiers PXD000484 and PXD000485. Statistical analysis showed differential abundance of 99 proteins, of which a subset of 4 proteins was selected through a multivariate step-down to develop a predictor for tamoxifen treatment outcome. The 4-protein signature significantly predicted poor outcome patients in the test set, independent of predictive histopathological characteristics (hazard ratio [HR] = 2.17; 95% confidence interval [CI] = 1.15 to 4.17; multivariate Cox regression p value = 0.017). Immunohistochemical (IHC) staining of PDCD4, one of the signature proteins, on an independent set of formalin-fixed paraffin-embedded tumor tissues provided and independent technical validation (HR = 0.72; 95% CI = 0.57 to 0.92; multivariate Cox regression p value = 0.009). We hereby report the first validated protein predictor for tamoxifen treatment outcome in recurrent ER-positive breast cancer. IHC further showed that PDCD4 is an independent marker. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.