Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
J Mol Diagn. 2020 Jul;22(7):920-933. doi: 10.1016/j.jmoldx.2020.04.205. Epub 2020 Apr 30.
Patients with incurable cancer usually receive palliative treatment with significant toxicity and limited efficacy. Methylation analysis of circulating cell-free DNA (ccfDNA) in blood from cancer patients represents a promising approach for minimally invasive, real-time monitoring of treatment response. Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) methylation was analyzed in N = 8865 malignant and N = 746 normal adjacent tissues across 33 different malignancies from The Cancer Genome Atlas. Furthermore, we performed quantitative SHOX2 and SEPT9 ccfDNA methylation analysis in plasma obtained before and consecutively during treatment from prospectively enrolled N = 115 patients with various advanced cancers. SHOX2 and/or SEPT9 hypermethylation in malignant tissues is present in various carcinomas, sarcoma, melanoma, brain tumors, mesothelioma, and hematopoietic malignancies. Among the prospectively enrolled cancer patients, 61% (70/115) of patients had a baseline-positive blood cumulative ccfDNA methylation score (CMS) and were eligible for response monitoring. Dynamic changes of CMS during treatment were strongly associated with treatment response. A CMS increase indicated response up to 80 days before conventional monitoring. SHOX2 and SEPT9 ccfDNA methylation represents a pan-cancer biomarker and has the potential to be a powerful tool for monitoring treatment response in patients with solid tumors and lymphomas. The early identification of nonresponders might allow for a timely change of treatment regimen.
患有绝症的患者通常接受具有显著毒性和有限疗效的姑息治疗。从癌症患者的血液中循环无细胞 DNA（ccfDNA）的甲基化分析代表了一种有前途的微创、实时监测治疗反应的方法。在来自癌症基因组图谱的 33 种不同恶性肿瘤中，分析了 N = 8865 例恶性肿瘤和 N = 746 例正常相邻组织中的短体同源盒 2（SHOX2）和 septin 9（SEPT9）甲基化。此外，我们对前瞻性纳入的 N = 115 例各种晚期癌症患者的血浆进行了 SHOX2 和 SEPT9 ccfDNA 甲基化的定量分析。在各种癌、肉瘤、黑色素瘤、脑肿瘤、间皮瘤和造血恶性肿瘤中，恶性组织中存在 SHOX2 和/或 SEPT9 高甲基化。在前瞻性纳入的癌症患者中，有 61%（70/115）的患者基线阳性血累积 ccfDNA 甲基化评分（CMS），有资格进行反应监测。治疗过程中 CMS 的动态变化与治疗反应强烈相关。CMS 增加表明在常规监测前 80 天就有反应。SHOX2 和 SEPT9 ccfDNA 甲基化是一种泛癌生物标志物，有可能成为监测实体瘤和淋巴瘤患者治疗反应的有力工具。早期识别无反应者可能有助于及时改变治疗方案。
