Department of Biology, Georgia State University, Atlanta, GA, USA.
Novazoi Theranostics, Inc., Rolling Hills Estates, CA, USA.
Sci Rep. 2017 Mar 21;7(1):262. doi: 10.1038/s41598-017-00363-w.
Centrosome amplification (CA) is a hallmark of cancer, observable in ≥75% of breast tumors. CA drives aggressive cellular phenotypes such as chromosomal instability (CIN) and invasiveness. Thus, assessment of CA may offer insights into the prognosis of breast cancer and identify patients who might benefit from centrosome declustering agents. However, it remains unclear whether CA is correlated with clinical outcomes after adjusting for confounding factors. To gain insights, we developed a signature, "CA20", comprising centrosome structural genes and genes whose dysregulation is implicated in inducing CA. We found that CA20 was a significant independent predictor of worse survival in two large independent datasets after adjusting for potentially confounding factors. In multivariable analyses including both CA20 and CIN25 (a gene expression-based score that correlates with aneuploidy and has prognostic value in many types of cancer), only CA20 was significant, suggesting CA20 captures the risk-predictive information of CIN25 and offers information beyond it. CA20 correlated strongly with CIN25, so a high CA20 score may reflect tumors with high CIN and potentially other aggressive features that may require more aggressive treatment. Finally, we identified processes and pathways differing between CA20-low and high groups that may be valuable therapeutic targets.
中心体扩增（CA）是癌症的一个标志，在≥75%的乳腺癌肿瘤中都可观察到。CA 驱动了具有侵袭性的细胞表型，如染色体不稳定（CIN）。因此，CA 的评估可能有助于了解乳腺癌的预后，并确定可能受益于中心体解聚剂的患者。然而，在调整混杂因素后，CA 是否与临床结果相关仍不清楚。为了深入了解这一点，我们开发了一个特征签名，称为“CA20”，包含中心体结构基因和那些失调与诱导 CA 相关的基因。我们发现，在调整了潜在混杂因素后，CA20 是两个大型独立数据集生存不良的显著独立预测因子。在包括 CA20 和 CIN25（一种与非整倍体相关且在许多类型的癌症中具有预后价值的基于基因表达的评分）的多变量分析中，只有 CA20 具有统计学意义，这表明 CA20 捕捉到了 CIN25 的风险预测信息，并提供了超出其本身的信息。CA20 与 CIN25 强烈相关，因此高 CA20 评分可能反映了具有高 CIN 和潜在其他侵袭性特征的肿瘤，这些肿瘤可能需要更积极的治疗。最后，我们确定了 CA20 低和高组之间存在差异的过程和途径，这些过程和途径可能是有价值的治疗靶点。
