O'Brien Sallyann L, Fagan Ailís, Fox Edward J P, Millikan Robert C, Culhane Aedín C, Brennan Donal J, McCann Amanda H, Hegarty Shauna, Moyna Siobhan, Duffy Michael J, Higgins Desmond G, Jirström Karin, Landberg Göran, Gallagher William M
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Int J Cancer. 2007 Apr 1;120(7):1434-43. doi: 10.1002/ijc.22413.
DNA microarrays have the potential to classify tumors according to their transcriptome. Tissue microarrays (TMAs) facilitate the validation of biomarkers by offering a high-throughput approach to sample analysis. We reanalyzed a high profile breast cancer DNA microarray dataset containing 96 tumor samples using a powerful statistical approach, between group analyses. Among the genes we identified was centromere protein-F (CENP-F), a gene associated with poor prognosis. In a published follow-up breast cancer DNA microarray study, comprising 295 tumour samples, we found that CENP-F upregulation was significantly associated with worse overall survival (p<0.001) and reduced metastasis-free survival (p<0.001). To validate and expand upon these findings, we used 2 independent breast cancer patient cohorts represented on TMAs. CENP-F protein expression was evaluated by immunohistochemistry in 91 primary breast cancer samples from cohort I and 289 samples from cohort II. CENP-F correlated with markers of aggressive tumor behavior including ER negativity and high tumor grade. In cohort I, CENP-F was significantly associated with markers of CIN including cyclin E, increased telomerase activity, c-Myc amplification and aneuploidy. In cohort II, CENP-F correlated with VEGFR2, phosphorylated Ets-2 and Ki67, and in multivariate analysis, was an independent predictor of worse breast cancer-specific survival (p=0.036) and overall survival (p=0.040). In conclusion, we identified CENP-F as a biomarker associated with poor outcome in breast cancer and showed several novel associations of biological significance.
DNA微阵列有潜力根据肿瘤的转录组对其进行分类。组织微阵列(TMA)通过提供一种高通量的样本分析方法,促进了生物标志物的验证。我们使用一种强大的统计方法——组间分析,重新分析了一个包含96个肿瘤样本的备受瞩目的乳腺癌DNA微阵列数据集。我们鉴定出的基因中有着丝粒蛋白F(CENP-F),这是一个与预后不良相关的基因。在一项已发表的后续乳腺癌DNA微阵列研究中,该研究包含295个肿瘤样本,我们发现CENP-F上调与较差的总生存期(p<0.001)和无转移生存期缩短(p<0.001)显著相关。为了验证并扩展这些发现,我们使用了TMA上所代表的2个独立的乳腺癌患者队列。通过免疫组织化学在队列I的91个原发性乳腺癌样本和队列II的289个样本中评估CENP-F蛋白表达。CENP-F与侵袭性肿瘤行为的标志物相关,包括雌激素受体阴性和高肿瘤分级。在队列I中,CENP-F与染色体不稳定(CIN)的标志物显著相关,包括细胞周期蛋白E、端粒酶活性增加、c-Myc扩增和非整倍体。在队列II中,CENP-F与血管内皮生长因子受体2(VEGFR2)、磷酸化Ets-2和Ki67相关,并且在多变量分析中,是较差的乳腺癌特异性生存期(p=0.036)和总生存期(p=0.040)的独立预测因子。总之,我们鉴定出CENP-F是一种与乳腺癌不良预后相关的生物标志物,并展示了几种具有生物学意义的新关联。