Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany.
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Clin Colorectal Cancer. 2018 Jun;17(2):e385-e393. doi: 10.1016/j.clcc.2018.02.008. Epub 2018 Feb 23.
New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 (PITX2) promoter methylation in CRC patients.
Data of 2 independent cohorts were investigated. Tissue specimens of cohort A (n = 179) were analyzed for their methylation in the PITX2 promoter region using quantitative methylation-specific polymerase chain reaction and compared with publicly available data (PITX2 promoter methylation and PITX2 mRNA expression levels) from "The Cancer Genome Atlas Research Network" (cohort B, n = 443). Data were correlated with clinicopathological parameters and outcome.
Tumor samples of both cohorts showed a decreased PITX2 promoter methylation level (both P < .001) compared with nonmalignant tissue. Additionally, PITX2 promoter hypomethylation was prognostic in univariate and multivariate analysis (hazard ratio [HR], 1.97 [95% confidence interval (CI), 1.12-3.47], P = .018 and HR, 1.89 [95% CI, 1.09-3.29], P = .023), and Kaplan-Meier analysis (median overall survival, 53.2 vs. 70.4 months, P = .004). Subanalysis of high-risk vs. low-risk stage II CRC patients also showed a PITX2 hypomethylation of the promoter region in the high-risk group (P = .006).
Our results suggest a prognostic role of PITX2 promoter methylation in CRC as biomarker for risk stratification in stage II CRC patients although the results need to be independently validated.
新的治疗方式和对复杂肿瘤遗传景观的深入了解改善了结直肠癌（CRC）患者的预后。尽管如此，最近提出了更多考虑个体肿瘤特征的个体化治疗方案，需要预测预后的生物标志物。因此，我们评估了配对同源框转录因子 2（PITX2）启动子甲基化在 CRC 患者中的预后潜力。
我们对两个独立队列的数据进行了研究。使用定量甲基化特异性聚合酶链反应分析队列 A（n=179）组织标本中 PITX2 启动子区域的甲基化情况，并与来自“癌症基因组图谱研究网络”的公开数据（PITX2 启动子甲基化和 PITX2 mRNA 表达水平）（队列 B，n=443）进行比较。我们将数据与临床病理参数和预后相关联。
两个队列的肿瘤样本与非恶性组织相比，PITX2 启动子甲基化水平均降低（均 P<0.001）。此外，PITX2 启动子低甲基化在单因素和多因素分析中具有预后意义（危险比[HR]，1.97[95%置信区间（CI），1.12-3.47]，P=0.018 和 HR，1.89[95% CI，1.09-3.29]，P=0.023），Kaplan-Meier 分析（中位总生存期，53.2 与 70.4 个月，P=0.004）。高危与低危 II 期 CRC 患者的亚组分析也显示高危组 PITX2 启动子区域的低甲基化（P=0.006）。
尽管结果需要独立验证，但我们的研究结果提示 PITX2 启动子甲基化在 CRC 中具有预后作用，可作为 II 期 CRC 患者风险分层的生物标志物。
