Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi, Yokohama, Japan.
Eur J Surg Oncol. 2013 Jun;39(6):655-61. doi: 10.1016/j.ejso.2013.02.023. Epub 2013 Mar 21.
We evaluated the methylation patterns of histone H3 lysine 27 (H3K27), H3 lysine 36 (H3K36) and the expression of H3K27 methylase EZH2 in patients with colorectal carcinomas with metachronous liver metastasis to search for biomarkers identifying these patients.
Double 2-mm core tissue microarrays were made from 54 paraffin-embedded samples of primary colorectal adenocarcinomas and corresponding liver metastases and examined using an immunohistochemical analysis of dimethylation and trimethylation in H3K27, H3K36 and EZH2. Positive tumor cell staining for each histone modification (H-score) was used to classify patients into low- and high-staining groups, which were then examined to identify any correlations between the clinicopathological parameters and the clinical outcomes.
The H-scores of H3K27me2 were lower in the liver metastases than in the corresponding primary tumors, while the H-scores of H3K36me2 were higher in the liver metastases than in the corresponding primary tumors (P < 0.001). H3K27me2 in the primary tumors correlated with tumor size (P = 0.016), H3K36me2 in the primary tumors correlated with histological type (P = 0.038), and H3K36me3 in the primary tumors correlated with lymph node metastasis (P = 0.017). In addition, lower levels of H3K27me2 in the primary tumors correlated with poorer survival rates (P = 0.039). The multivariate survival analysis showed that the H3K27me2 status is an independent prognostic factor for colorectal cancer patients (P = 0.047).
Our findings suggest that the methylation level of H3K27me2 detected with immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.
我们评估了组蛋白 H3 赖氨酸 27（H3K27）、H3 赖氨酸 36（H3K36）的甲基化模式以及 H3K27 甲基转移酶 EZH2 在结直肠癌伴异时性肝转移患者中的表达，以寻找识别这些患者的生物标志物。
从 54 例石蜡包埋的原发性结直肠腺癌及其相应的肝转移组织中制作了双层 2mm 组织微阵列，并使用 H3K27、H3K36 和 EZH2 的二甲基化和三甲基化免疫组织化学分析进行检查。每个组蛋白修饰（H 评分）的阳性肿瘤细胞染色用于将患者分为低染色组和高染色组，然后检查这些组与临床病理参数和临床结果之间的任何相关性。
H3K27me2 在肝转移中的 H 评分低于相应的原发性肿瘤，而 H3K36me2 在肝转移中的 H 评分高于相应的原发性肿瘤（P<0.001）。原发性肿瘤中的 H3K27me2 与肿瘤大小相关（P=0.016），原发性肿瘤中的 H3K36me2 与组织学类型相关（P=0.038），原发性肿瘤中的 H3K36me3 与淋巴结转移相关（P=0.017）。此外，原发性肿瘤中 H3K27me2 水平较低与生存率降低相关（P=0.039）。多变量生存分析显示，H3K27me2 状态是结直肠癌患者的独立预后因素（P=0.047）。
我们的研究结果表明，免疫组织化学检测的 H3K27me2 甲基化水平可能是结直肠癌异时性肝转移的独立预后因素。
