Sun Ling-Ling, Wu Jian-Yi, Wu Zhi-Yong, Shen Jin-Hui, Xu Xiu-E, Chen Bo, Wang Shao-Hong, Li En-Min, Xu Li-Yan
Institute of Oncologic Pathology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China; Department of Pathology, Shaoyang Central Hospital, Affiliated Shaoyang Hospital of University of South China, Shaoyang, Hunan, China.
Int J Cancer. 2015 Mar 15;136(6):E569-77. doi: 10.1002/ijc.29211. Epub 2014 Sep 24.
It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications. GASC1, member of the histone demethylases affecting heterochromatin formation and transcriptional repression, has been found to be dysregulation in many types of cancers including breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia. In this study, we examined the expression of GASC1 and certain GASC1-targeted genes (KLF4, MYC, SOX2, PPARG, MDM2, and NANOG) and identified a three-gene prognostic signature (PPARG, MDM2, and NANOG), using risk scores based on immunohistochemical analyses of 149 tumor specimens from patients with esophageal squamous cell carcinoma (ESCC). The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients. We validated the predictive value of the three-gene signature in a second independent cohort of 101 patients with ESCC in order to determine whether it had predictive value. The results were similar to those in 149 patients. According to multivariate Cox proportional hazards analyses, the predictive model of a three-gene signature was an independent predictor for OS (p = 0.005 in cohort 1, p = 0.025 in cohort 2). In addition, ROC analysis indicated that the predictive ability of the three-gene model was more robust than that of a single biomarker. Therefore, our three-gene signature is closely associated with OS among patients with ESCC and may serve as a predictor for the poor prognosis of ESCC patients.
越来越明显的是，癌症的发展不仅取决于基因改变，还取决于涉及组蛋白修饰的表观遗传变化。GASC1是影响异染色质形成和转录抑制的组蛋白去甲基化酶成员，已发现在包括乳腺癌、前列腺癌、转移性肺肉瘤样癌和白血病在内的多种癌症中存在失调。在本研究中，我们检测了GASC1和某些GASC1靶向基因（KLF4、MYC、SOX2、PPARG、MDM2和NANOG）的表达，并基于对149例食管鳞状细胞癌（ESCC）患者肿瘤标本的免疫组化分析，使用风险评分确定了一个三基因预后特征（PPARG、MDM2和NANOG）。ESCC肿瘤中高风险三基因特征的存在与患者总生存期（OS）的降低显著相关。我们在第二个由101例ESCC患者组成的独立队列中验证了三基因特征的预测价值，以确定其是否具有预测价值。结果与149例患者的结果相似。根据多变量Cox比例风险分析，三基因特征的预测模型是OS的独立预测因子（队列1中p = 0.005，队列2中p = 0.025）。此外，ROC分析表明，三基因模型的预测能力比单一生物标志物更强。因此，我们的三基因特征与ESCC患者的OS密切相关，可能作为ESCC患者预后不良的预测指标。
