FOXM1 预测非肌肉浸润性膀胱癌的疾病进展。
FOXM1 predicts disease progression in non-muscle invasive bladder cancer.
机构信息
Department of Hematology and Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
Department of Urology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
出版信息
J Cancer Res Clin Oncol. 2018 Sep;144(9):1701-1709. doi: 10.1007/s00432-018-2694-5. Epub 2018 Jun 29.
PURPOSE
The proto-oncogene forkhead box M1 (FOXM1) is associated with poor survival in many cancers. The impact of FOXM1 expression on progression-free survival (PFS) of non-muscle invasive bladder cancer (NMIBC) has not yet been investigated. The differential expression of FOXM1 between the different molecular NMIBC subtypes has further been assessed.
METHODS
Transcript levels of FOXM1 and MKI67 were determined in 460 NMIBC patients (UROMOL cohort) by RNA-Seq and validated in silico by the Chungbuk and Lund cohort (n = 277). FOXM1 and MKI67 cutoffs were identified by the minimal p value method. Variables were evaluated by multivariable Cox regression analyses in order to identify independent predictors.
RESULTS
FOXM1 is an independent predictor for PFS superior to current histological, clinical and molecular staging methods. Patients with high FOXM1 expression have a 6- to 8-fold higher risk of progression in multivariable analysis (p < 0.03). Highest transcript levels were found in the Class 2 and genomically unstable molecular NMIBC subtype (p < 0.03). The proto-oncogene further positively correlated with tumor grade and stage. NMIBCs with high FOXM1 expression showed a PFS advantage when treated with intravesical BCG instillation.
CONCLUSION
FOXM1 is a highly prognostic marker for disease progression of NMIBC superior to current histological, clinical and molecular staging methods and MKI67. It is mainly expressed in the Class 2 and genomically unstable molecular bladder cancer subtypes. Its role in drug resistance development makes FOXM1 valuable biomarker for NMIBC risk stratification.
目的
原癌基因叉头框 M1（FOXM1）与许多癌症的不良预后相关。FOXM1 表达对非肌肉浸润性膀胱癌（NMIBC）无进展生存期（PFS）的影响尚未得到研究。进一步评估了 FOXM1 在不同分子 NMIBC 亚型之间的差异表达。
方法
通过 RNA-Seq 测定了 460 例 NMIBC 患者（UROMOL 队列）中 FOXM1 和 MKI67 的转录水平，并通过 Chungbuk 和 Lund 队列（n=277）进行了计算机验证。通过最小 p 值法确定 FOXM1 和 MKI67 的截断值。通过多变量 Cox 回归分析评估变量，以确定独立预测因子。
结果
FOXM1 是 PFS 的独立预测因子，优于当前的组织学、临床和分子分期方法。多变量分析中，高 FOXM1 表达患者的进展风险增加 6-8 倍（p<0.03）。在 Class 2 和基因组不稳定的分子 NMIBC 亚型中发现最高的转录水平（p<0.03）。原癌基因进一步与肿瘤分级和分期呈正相关。高 FOXM1 表达的 NMIBC 在用膀胱内 BCG 灌注治疗时显示出 PFS 优势。
结论
FOXM1 是 NMIBC 疾病进展的高度预后标志物，优于当前的组织学、临床和分子分期方法以及 MKI67。它主要在 Class 2 和基因组不稳定的分子膀胱癌亚型中表达。其在耐药性发展中的作用使 FOXM1 成为 NMIBC 风险分层的有价值的生物标志物。
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