Ojo Diane, Seliman Maryam, Tang Damu
Division of Nephrology, Department of Medicine, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada.
Father Sean O'Sullivan Research Institute, St. Joseph's Hospital, Hamilton, Ontario, Canada.
BBA Clin. 2017 Aug 24;8:56-65. doi: 10.1016/j.bbacli.2017.07.004. eCollection 2017 Dec.
We report three signatures produced from gene copy number increase (GCN-Increase) and their effects on patients with breast cancer (BC). In the Metabric dataset (n = 2059, cBioPortal), GCN-Increase occurs preferentially or mutual exclusively with mutations in , , and . These genomic alterations constitute a signature (SigMut) that significantly correlates with reductions in overall survival (OS) in BC patients (n = 1980; p = 1.081e - 6). Additionally, GCN-Increase is associated with 4220 differentially expressed genes (DEGs). These DEGs are enriched in activation of the pathways regulating cell cycle progression, RNA transport, ribosome biosynthesis, DNA replication, and in downregulation of the pathways related to extracellular matrix. These DEGs are thus likely to facilitate the proliferation and metastasis of BC cells. Additionally, through forward (FWD) and backward (BWD) stepwise variate selections among the top 160 downregulated and top 200 upregulated DEGs using the Cox regression model, a 6-gene (SigFWD) and a 50-gene (SigBWD) signature were derived. Both signatures robustly associate with decreases in OS in BC patients within the Curtis (n = 1980; p = 6.16e - 11 for SigFWD; p = 1.06e - 10, for SigBWD) and TCGA cohort (n = 817; p = 4.53e - 4 for SigFWD and p = 0.00525 for SigBWD). After adjusting for known clinical factors, SigMut (HR 1.21, p = 0.0297), SigBWD (HR 1.25, p = 0.0263), and likely SigFWD (HR 1.17, p = 0.062) remain independent risk factors of BC deaths. Furthermore, the proportion of patients positive for these signatures is significantly increased in ER -, Her2-enriched, basal-like, and claudin-low BCs compared to ER + and luminal BCs. Collectively, these GCN-Increase-derived signatures may have clinical applications in management of patients with BC.
我们报告了由基因拷贝数增加（GCN-Increase）产生的三个特征及其对乳腺癌（BC）患者的影响。在Metabric数据集（n = 2059，cBioPortal）中，GCN-Increase优先或相互排斥地与 、 和 中的突变同时出现。这些基因组改变构成了一个特征（SigMut），该特征与BC患者（n = 1980；p = 1.081e - 6）的总生存期（OS）降低显著相关。此外，GCN-Increase与4220个差异表达基因（DEG）相关。这些DEG在调节细胞周期进程、RNA转运、核糖体生物合成、DNA复制的途径激活中富集，并在与细胞外基质相关的途径下调中富集。因此，这些DEG可能促进BC细胞的增殖和转移。此外，通过使用Cox回归模型在前160个下调和前200个上调的DEG中进行向前（FWD）和向后（BWD）逐步变量选择，得出了一个6基因（SigFWD）和一个50基因（SigBWD）特征。在Curtis队列（n = 198)）和TCGA队列（n = 817）中，这两个特征均与BC患者的OS降低密切相关（SigFWD：p = 6.16e - 11；SigBWD：p = 1.06e - 10）。在调整已知临床因素后，SigMut（HR 1.21，p = 0.0297）、SigBWD（HR 1.25，p = 0.0263）以及可能的SigFWD（HR 1.17，p = 0.062）仍然是BC死亡的独立危险因素。此外，与ER +和管腔型BC相比，这些特征呈阳性的患者比例在ER -、Her2富集型、基底样和claudin低表达型BC中显著增加。总体而言，这些源自GCN-Increase的特征可能在BC患者的管理中具有临床应用价值。
