Alonso-Dominguez Juan M, Casado Luis Felipe, Anguita Eduardo, Gomez-Casares Maria Teresa, Buño Ismael, Ferrer-Marín Francisca, Arenas Alicia, Del Orbe Rafael, Ayala Rosa, Llamas Pilar, Salgado Rocio N, Osorio Santiago, Sanchez-Godoy Pedro, Burgaleta Carmen, Mahíllo-Fernández Ignacio, Garcia-Gutierrez Valentin, Steegmann Juan Luis, Martinez-Lopez Joaquín
Hospital Universitario Fundación Jiménez Díaz, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), UAM, Madrid, Spain.
Hospital Virgen de la Salud, Toledo, Spain.
PLoS One. 2017 Jul 13;12(7):e0181366. doi: 10.1371/journal.pone.0181366. eCollection 2017.
Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.
patched 同源物 1 基因（PTCH1）的表达以及 PTCH1 与 Smoothened（SMO）表达的比值已被提议作为慢性髓性白血病（CML）患者对伊马替尼反应的预后标志物。我们使用简化的定量聚合酶链反应（qPCR）方法，在一个由 101 例慢性期（CP）CML 患者组成的实际队列中比较了这些测量值，并在竞争风险分析中证实了每个指标的预后能力。在诊断时测量外周血样本中的基因表达水平。PTCH1/SMO 比值并未提高 PTCH1 的预后能力（受试者操作特征曲线下面积分别为 0.71 和 0.72）。为了减少待分析的基因数量，选择了 PTCH1 作为测量指标。PTCH1 高表达组和低表达组的伊马替尼治疗失败（IF）累积发生率显著不同，IF 定义为因疗效不佳而停用伊马替尼（4 年时分别为 5%和 25%，P = 0.013），达到主要分子反应的概率（第一年时分别为 81%和 53%，P = 0.02），以及早期分子失败的比例（分别为 14%和 43%，P = 0.015）。所有进展至晚期阶段（n = 3）和 CML 相关死亡（n = 2）均发生在 PTCH1 低表达组（两项比较的 P 均<0.001）。PTCH1 是预测 IF 的独立预后因素。我们还验证了先前发表的 PTCH1 表达阈值。因此，我们通过应用更严格的统计分析证实，PTCH1 表达可预测 CP 期 CML 患者对伊马替尼的反应。因此，PTCH1 表达是预测 CP 期 CML 患者对伊马替尼反应的一个有前景的分子标志物。
