Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.
Clin Cancer Res. 2010 May 15;16(10):2811-8. doi: 10.1158/1078-0432.CCR-09-2717. Epub 2010 May 11.
Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic aberrations such as DNA methylation have been shown to be significant prognostic biomarkers of disease outcome. In this study, we evaluated the significance of a quantitative epigenetic multimarker panel analysis of primary tumors to predict local recurrence in rectal cancer patients from a retrospective multicenter clinical trial.
Primary tumors were studied from patients enrolled in the trial who underwent total mesorectal excision for rectal cancer (n=325). Methylation levels of seven methylated-in-tumor (MINT) loci were assessed by absolute quantitative assessment of methylated alleles. Unsupervised random forest clustering of quantitative MINT methylation data was used to show subclassification into groups with matching methylation profiles.
Variable importance parameters [Gini-Index (GI)] of the clustering algorithm indicated MINT3 and MINT17 (GI, 20.2 and 20.7, respectively) to be informative for patient grouping compared with the other MINT loci (highest GI, 12.2). When using this two-biomarker panel, four different patient clusters were identified. One cluster containing 73% (184 of 251) of the patients was at significantly increased risk of local recurrence (hazard ratio, 10.23; 95% confidence interval, 1.38-75.91) in multivariate analysis, corrected for standard prognostic factors of rectal cancer. This group showed a significantly higher local recurrence probability than patients receiving preoperative radiation (P<0.0001).
Quantitative epigenetic subclassification of rectal cancers has clinical utility in distinguishing tumors with increased risk for local recurrence and may help tailor treatment regimens for locoregional control.
对于接受直肠肿瘤初次切除的患者，局部区域疾病复发的风险评估在术前治疗计划中具有重要价值。表观遗传改变，如 DNA 甲基化，已被证明是疾病预后的重要生物标志物。在这项研究中，我们评估了对原发性肿瘤进行定量表观遗传多标志物分析的意义，以预测来自回顾性多中心临床试验的直肠癌患者的局部复发。
对参加直肠肿瘤全直肠系膜切除术的患者（n=325）的原发性肿瘤进行研究。通过对甲基化等位基因的绝对定量评估，评估七个肿瘤中甲基化（MINT）位点的甲基化水平。采用无监督随机森林聚类对定量 MINT 甲基化数据进行聚类，以显示匹配甲基化谱的分组。
聚类算法的变量重要性参数[基尼指数（GI）]表明，与其他 MINT 基因座相比，MINT3 和 MINT17（GI 分别为 20.2 和 20.7）在提示患者分组方面具有信息性（最高 GI 为 12.2）。当使用这两个生物标志物面板时，鉴定出四个不同的患者亚群。包含 73%（251 例中的 184 例）患者的一个亚群在多变量分析中局部复发风险显著增加（危险比，10.23；95%置信区间，1.38-75.91），该风险比经直肠肿瘤标准预后因素校正。该亚群的局部复发概率显著高于接受术前放疗的患者（P<0.0001）。
直肠肿瘤的定量表观遗传分类在区分局部复发风险增加的肿瘤方面具有临床实用性，并且可能有助于制定局部区域控制的治疗方案。
