Magbanua Mark Jesus M, Rugo Hope S, Hauranieh Louai, Roy Ritu, Scott Janet H, Lee Jen Chieh, Hsiao Feng, Sosa Eduardo V, Van't Veer Laura, Esserman Laura J, Park John W
1Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA USA.
2Helen Diller Family Comprehensive Cancer Center and Computational Biology and Informatics, University of California, San Francisco, San Francisco, CA USA.
NPJ Breast Cancer. 2018 Sep 5;4:31. doi: 10.1038/s41523-018-0083-5. eCollection 2018.
Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools ( = 45) appeared less aberrant than the corresponding primary tumors (PT, = 16). mutations were detected in 26% of DTC pools ( = 53), none of them were shared with matched PTs. Expression profiling of DTC pools ( = 30) confirmed the upregulation of expression and certain oncogenes (e.g., and ), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial-mesenchymal properties (high and expression), and (2) basal-like with proliferative/stem cell-like phenotype (low and high expression). We observed high discordance between (40%) and (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, , , and were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.
骨髓中播散性肿瘤细胞(DTCs)的检测是一个已确定的负面预后因素。我们从早期乳腺癌患者中分离出少量(约20个)EPCAM阳性DTCs用于基因组分析。DTC样本库(n = 45)的全基因组拷贝数图谱显示,其异常程度低于相应的原发性肿瘤(PT,n = 16)。在26%的DTC样本库(n = 53)中检测到突变,其中没有一个与匹配的原发性肿瘤共享。DTC样本库(n = 30)的表达谱分析证实了某些基因和癌基因(如 和 )的上调,以及造血特征的缺失。观察到两种表达亚型:(1)具有双重上皮-间质特性的管腔型(高 和 表达),以及(2)具有增殖/干细胞样表型的基底样型(低 和高 表达)。我们观察到DTC样本库中的 (40%)和 (43%)表达与相应原发性肿瘤的临床ER和HER2状态之间存在高度不一致,这表明在向骨髓播散过程中生物标志物状态具有可塑性。将DTC样本库的表达谱与转移性乳腺癌患者循环肿瘤细胞(CTC)的现有数据进行比较,发现DTC中的基因表达特征与CTC不同。例如,相对于CTC, 、 和 在DTC样本库中上调。综上所述,对合并的DTCs分析揭示了分子异质性、与相应原发性肿瘤可能的基因差异以及两个不同的亚群。需要在更大的队列中进行验证,以确认这些分子亚型的存在,并评估它们的生物学和临床意义。
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