Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
J Clin Oncol. 2010 Mar 10;28(8):1358-65. doi: 10.1200/JCO.2009.24.5639. Epub 2010 Feb 8.
PURPOSE Differences in cellular levels of histone modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three histone modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
组蛋白修饰的细胞水平差异可预测某些癌症的临床结局。本研究旨在探讨胰腺腺癌中三种组蛋白修饰的预后和预测价值。
对两个胰腺腺癌队列的组织微阵列（TMA）进行了检测，包括放射治疗肿瘤学组（RTOG）试验 RTOG 9704 中 195 例患者队列的 TMA，该试验为多中心、三期、随机治疗试验，比较了辅助吉西他滨与氟尿嘧啶的疗效；以及加利福尼亚大学洛杉矶分校医疗中心 140 例 I 期或 II 期癌症患者的 TMA。采用组蛋白 H3 赖氨酸 4 二甲基化（H3K4me2）、组蛋白 H3 赖氨酸 9 二甲基化（H3K9me2）和组蛋白 H3 赖氨酸 18 乙酰化（H3K18ac）的免疫组化方法进行检测。每个组蛋白修饰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，然后与临床病理参数和临床结局指标相关联。
在单变量和多变量模型中，低水平的 H3K4me2、H3K9me2 或 H3K18ac 均为生存不良的显著且独立的预测因子，而 H3K4me2 和/或 H3K18ac 的联合低水平是加利福尼亚大学洛杉矶分校队列中总生存的最显著预测因子（危险比，2.93；95%CI，1.78 至 4.82）。在亚组分析中，对于淋巴结阴性癌症患者或接受氟尿嘧啶辅助治疗而非吉西他滨的 RTOG 9704 患者，组蛋白水平可预测生存。
组蛋白修饰的细胞水平定义了胰腺腺癌以前未被识别的亚组，这些亚组具有不同的表观遗传表型和临床结局，并代表了预后和预测生物标志物，可以为临床决策提供信息，包括氟尿嘧啶化疗的使用。
