Uhl Barbara, Dietrich Dimo, Branchi Vittorio, Semaan Alexander, Schaefer Pauline, Gevensleben Heidrun, Rostamzadeh Babak, Lingohr Philipp, Schäfer Nico, Kalff Jörg C, Kristiansen Glen, Matthaei Hanno
Institute of Pathology, University of Bonn, Bonn, Germany.
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Germany.
PLoS One. 2016 Oct 31;11(10):e0165769. doi: 10.1371/journal.pone.0165769. eCollection 2016.
Biliary tract cancers (BTC) are rare but highly aggressive malignant epithelial tumors. In order to improve the outcome in this lethal disease, novel biomarkers for diagnosis, prognosis, and therapy response prediction are urgently needed. DNA promoter methylation of PITX2 variants (PITX2ab, PITX2c) and intragenic methylation of the PITX2 adjacent non-coding RNA (PANCR) were investigated by methylations-specific qPCR assays in formalin-fixed paraffin-embedded tissue from 80 patients after resection for BTC. Results were correlated with clinicopathologic data and outcome. PITX2 variants and PANCR showed significant hypermethylation in tumor vs. normal adjacent tissue (p < 0.001 and p = 0.015), respectively. In survival analysis, dichotomized DNA methylation of variant PITX2c and PANCR were significantly associated with overall survival (OS). Patients with high tumor methylation levels of PITX2c had a shorter OS compared to patients with low methylation (12 vs. 40 months OS; HR 2.48 [1.38-4.48], p = 0.002). In contrast, PANCR hypermethylation was associated with prolonged survival (25 vs. 19 months OS; HR 0.54 [0.30-0.94], p = 0.015) and qualified as an independent prognostic factor on multivariate analysis. The biomarkers investigated in this study may help to identify BTC subpopulations at risk for worse survival. Further studies are needed to evaluate if PITX2 might be a clinically useful biomarker for an optimized and individualized treatment.
胆道癌（BTC）是一种罕见但侵袭性很强的恶性上皮肿瘤。为了改善这种致命疾病的治疗效果，迫切需要用于诊断、预后及预测治疗反应的新型生物标志物。我们采用甲基化特异性定量PCR分析法，对80例接受BTC切除术后患者的福尔马林固定石蜡包埋组织中PITX2变体（PITX2ab、PITX2c）的DNA启动子甲基化及PITX2相邻非编码RNA（PANCR）的基因内甲基化进行了研究。研究结果与临床病理数据及预后相关。PITX2变体和PANCR在肿瘤组织与相邻正常组织中分别显示出显著的高甲基化（p < 0.001和p = 0.015）。在生存分析中，PITX2c变体和PANCR的二分DNA甲基化与总生存期（OS）显著相关。与低甲基化患者相比，PITX2c肿瘤甲基化水平高的患者OS较短（OS分别为12个月和40个月；HR 2.48 [1.38 - 4.48]，p = 0.002）。相反，PANCR高甲基化与生存期延长相关（OS分别为25个月和19个月；HR 0.54 [0.30 - 0.94]，p = 0.015），并且在多变量分析中被确定为独立的预后因素。本研究中所调查的生物标志物可能有助于识别生存预后较差的BTC亚群。还需要进一步研究来评估PITX2是否可能成为优化个体化治疗的临床有用生物标志物。
