Benard Anne, Goossens-Beumer Inès J, van Hoesel Anneke Q, Horati Hamed, Putter Hein, Zeestraten Eliane C M, van de Velde Cornelis J H, Kuppen Peter J K
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
PLoS One. 2014 Sep 22;9(9):e108265. doi: 10.1371/journal.pone.0108265. eCollection 2014.
Numerous changes in epigenetic mechanisms have been described in various types of tumors. In search for new biomarkers, we investigated the expression of Polycomb-group (PcG) proteins EZH2, BMI1 and SUZ12 and associated histone modification H3K27me3 in colorectal cancer. Nuclear expression of PcG proteins and histone modification H3K27me3 were immunohistochemically (IHC) stained on a tissue microarray (TMA), including 247 tumor tissues and 47 normal tissues, and scored using the semi-automated Ariol system. Tumor tissues showed higher expression of EZH2 (p = 0.05) and H3K27me3 (p<0.001) as compared to their normal counterparts. Combined marker trend analyses indicated that an increase in the number of markers showing high expression was associated with better prognosis. High expression of all four markers in the combined marker analyses was correlated with the best patient survival and the longest recurrence-free survival, with overall survival (p = 0.01, HR 0.42(0.21-0.84)), disease-free survival (p = 0.007, HR 0.23(0.08-0.67) and local recurrence-free survival (p = 0.02, HR 0.30(0.11-0.84)). In conclusion, we found that expression of PcG proteins and H3K27me3 showed prognostic value in our study cohort. Better stratification of patients was obtained by combining the expression data of the investigated biomarkers as compared to the individual markers, underlining the importance of investigating multiple markers simultaneously.
在各类肿瘤中已发现多种表观遗传机制的变化。为寻找新的生物标志物，我们研究了多梳蛋白家族（PcG）蛋白EZH2、BMI1和SUZ12以及相关组蛋白修饰H3K27me3在结直肠癌中的表达情况。在包含247个肿瘤组织和47个正常组织的组织微阵列（TMA）上，通过免疫组织化学（IHC）对PcG蛋白的核表达和组蛋白修饰H3K27me3进行染色，并使用半自动Ariol系统进行评分。与正常组织相比，肿瘤组织中EZH2（p = 0.05）和H3K27me3（p<0.001）的表达更高。联合标志物趋势分析表明，高表达标志物数量的增加与更好的预后相关。联合标志物分析中所有四种标志物的高表达与患者最佳生存率和最长无复发生存期相关，总体生存率（p = 0.01，HR 0.42(0.21 - 0.84)）、无病生存率（p = 0.007，HR 0.23(0.08 - 0.67)）和局部无复发生存率（p = 0.02，HR 0.30(0.11 - 0.84)）。总之，我们发现PcG蛋白和H3K27me3的表达在我们的研究队列中具有预后价值。与单个标志物相比，通过组合所研究生物标志物的表达数据能更好地对患者进行分层，这突出了同时研究多个标志物的重要性。
