Udali Silvia, De Santis Domenica, Ruzzenente Andrea, Moruzzi Sara, Mazzi Filippo, Beschin Greta, Tammen Stephanie A, Campagnaro Tommaso, Pattini Patrizia, Olivieri Oliviero, Guglielmi Alfredo, Choi Sang-Woon, Friso Simonetta
Department of Medicine, School of Medicine, University of Verona, Verona, Italy.
Department of Surgery, School of Medicine, University of Verona, Verona, Italy.
Front Genet. 2018 Jan 9;8:229. doi: 10.3389/fgene.2017.00229. eCollection 2017.
Colon cancer is one of the most frequent solid tumor and simultaneous diagnosis of primary colon cancer and liver metastases occurs in about one fourth of cases. The current knowledge on epigenetic signatures, especially those related to hydroxymethylation in primary cancer tissue, synchronous metastasis, and blood circulating cells is lacking. This study aimed to investigate both methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) status in the DNA of individual patients from colon cancer tissue, synchronous liver metastases, and in cancer-free colon and liver tissues and leukocytes. Patients undergoing curative surgery ( = 16) were enrolled and their laboratory and clinical history data collected. The contents of mCyt and hmCyt were determined by a liquid chromatography/mass spectrometry (LC/MS/MS) method in DNA extracted from primary colon cancer, synchronous hepatic metastatic tissues and homologous cancer-free tissues, i.e., colon and liver tissues as well as leukocytes. The mCyt and hmCyt levels were compared between cancerous and cancer-free tissues, and correlations between leukocytes and colon/liver tissues for both the mCyt and hmCyt levels were evaluated. The mCyt levels were similar in primary colon cancer and liver metastasis tissues (4.69 ± 0.37% vs. 4.77 ± 0.38%, respectively, = 0.535), and both primary and metastatic tissues were hypomethylated compared to cancer-free colon (4.98 ± 0.26%). The difference in the mCyt content between cancerous and cancer-free colon tissues was significantly lower in primary colon cancer ( = 0.004), but not in liver metastasis ( = 0.148). The hmCyt content was similar in primary colon cancer compared to liver metastasis (0.035%, C.I. 0.024-0.052% versus 0.035%, C.I. 0.021-0.058%, respectively, 0.905) and markedly depleted compared to the cancer-free colon (0.081%, C.I. 0.055-0.119%) with a statistically significant difference ( < 0.05) for both comparisons. The mCyt levels showed a borderline correlation between leukocytes and colon cancer tissue (Pearson's correlation coefficient = 0.51, = 0.052) while no correlations were detected for the hmCyt levels. In conclusion, primary colon cancer and synchronous liver metastasis tissues showed a similar epigenetic status but were significantly hypomethylated and hypohydroxymethylated as compared to homologous cancer-free colon tissues.
结肠癌是最常见的实体瘤之一，约四分之一的病例会同时诊断出原发性结肠癌和肝转移。目前缺乏关于表观遗传特征的知识，尤其是与原发性癌组织、同步转移和血液循环细胞中的羟甲基化相关的知识。本研究旨在调查结肠癌组织、同步肝转移以及癌旁结肠、肝组织和白细胞中个体患者DNA的甲基胞嘧啶（mCyt）和羟甲基胞嘧啶（hmCyt）状态。纳入接受根治性手术的患者（n = 16），并收集他们的实验室和临床病史数据。采用液相色谱/质谱（LC/MS/MS）法测定从原发性结肠癌、同步肝转移组织和同源癌旁组织（即结肠和肝组织以及白细胞）中提取的DNA中的mCyt和hmCyt含量。比较癌组织和癌旁组织之间的mCyt和hmCyt水平，并评估白细胞与结肠/肝组织之间mCyt和hmCyt水平的相关性。原发性结肠癌和肝转移组织中的mCyt水平相似（分别为4.69±0.37%和4.77±0.38%，P = 0.535），与癌旁结肠组织（4.98±0.26%）相比，原发性和转移组织均发生低甲基化。原发性结肠癌中癌组织与癌旁结肠组织之间的mCyt含量差异显著降低（P = 0.004），但在肝转移中差异不显著（P = 0.148）。原发性结肠癌与肝转移中的hmCyt含量相似（分别为0.035%，95%置信区间0.024 - 0.052%和0.035%，95%置信区间0.021 - 0.058%，P = 0.905），与癌旁结肠组织（0.081%，95%置信区间0.055 - 0.119%）相比明显减少，两次比较均具有统计学意义（P < 0.05）。mCyt水平在白细胞与结肠癌组织之间显示出临界相关性（Pearson相关系数 = 0.51，P = 0.052），而hmCyt水平未检测到相关性。总之，原发性结肠癌和同步肝转移组织显示出相似的表观遗传状态，但与同源癌旁结肠组织相比，均显著低甲基化和低羟甲基化。
