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通过检测循环中的甲基化GCM2和TMEM240监测乳腺癌进展。

Monitoring breast cancer progression through circulating methylated GCM2 and TMEM240 detection.

作者信息

Hung Chin-Sheng, Shen Hsieh-Tsung, Wang Pei-Yu, Su Chih-Ming, Hsu Wei-Wen, Chien Kuan-Yu, Han Cai-Sia, Liao Li-Min, Lin Ruo-Kai

机构信息

Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.

Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, 11031, Taiwan.

出版信息

Clin Epigenetics. 2025 Jul 21;17(1):128. doi: 10.1186/s13148-025-01939-4.

DOI:10.1186/s13148-025-01939-4

PMID:40691650

Abstract

BACKGROUND

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in women worldwide. Approximately 20-30% of women diagnosed with early-stage breast cancer eventually develop metastatic disease. Current biomarkers, such as CA15-3 and CEA, detect metastasis in only 60-80% of cases, underscoring the need for improved diagnostic tools. This study investigates the potential of circulating methylated GCM2 and TMEM240 as biomarkers for noninvasive monitoring of breast cancer progression.

METHODS

In a prospective study conducted in Taiwan, 396 patients were enrolled, alongside a retrospective study of 134 plasma samples from Western populations. cfDNA was extracted, subjected to sodium bisulfite conversion, and the methylation levels of GCM2 and TMEM240 were measured using QMSP. Monte Carlo analysis assigned 70% of the dataset to a training set and 30% to a validation set, repeated 1000 times. Performance metrics such as sensitivity, specificity, and accuracy were averaged to ensure robustness, supporting the use of combined GCM2 and TMEM240 for monitoring treatment response and tumor burden.

RESULTS

The training set, consisting of 166 breast cancer patients (13.3% with recurrence or metastasis), was utilized to establish the biomarker detection cutoff. Validation in a separate cohort of 325 patients (20% with recurrence or metastasis) demonstrated superior performance compared to CA15-3 and CEA, achieving 95.1% accuracy, 89.4% sensitivity, 96.5% specificity, 86.8% positive predictive value (PPV), and 97.3% negative predictive value (NPV). Monte Carlo analysis of the training data revealed an average sensitivity of 95.7%, specificity of 90.3%, and accuracy of 91.5%, while validation data achieved 92.8% sensitivity, 89.5% specificity, and 90.3% accuracy across 1000 replicates. Positive cases were significantly associated with late-stage disease (P < 0.001), larger tumors (P = 0.002), distant metastasis (P < 0.001), and disease progression (P < 0.001). For monitoring treatment response and tumor burden, decreased methylation levels were observed in patients responding well to treatment, whereas increased levels were noted in cases of cancer progression or prior to metastasis.

CONCLUSIONS

Overall, detecting methylated GCM2 and TMEM240 in plasma offers a novel, accurate, and noninvasive method for monitoring breast cancer progression.

摘要

背景

乳腺癌是全球女性中最常被诊断出的癌症，也是癌症相关死亡的第二大主要原因。大约20%-30%被诊断为早期乳腺癌的女性最终会发展为转移性疾病。目前的生物标志物，如CA15-3和CEA，仅在60%-80%的病例中检测到转移，这突出了对改进诊断工具的需求。本研究调查了循环甲基化GCM2和TMEM240作为乳腺癌进展无创监测生物标志物的潜力。

方法

在台湾进行的一项前瞻性研究中，招募了396名患者，同时对来自西方人群的134份血浆样本进行了回顾性研究。提取cfDNA，进行亚硫酸氢钠转化，并使用QMSP测量GCM2和TMEM240的甲基化水平。蒙特卡洛分析将70%的数据集分配到训练集，30%分配到验证集，重复1000次。对敏感性、特异性和准确性等性能指标进行平均以确保稳健性，支持联合使用GCM2和TMEM240监测治疗反应和肿瘤负荷。

结果

由166名乳腺癌患者（13.3%有复发或转移）组成的训练集用于建立生物标志物检测临界值。在另一组325名患者（20%有复发或转移）中的验证显示，与CA15-3和CEA相比，其性能更优，准确率达到95.1%，敏感性为89.4%，特异性为96.5%，阳性预测值（PPV）为86.8%，阴性预测值（NPV）为97.3%。对训练数据的蒙特卡洛分析显示，平均敏感性为95.7%，特异性为90.3%，准确率为91.5%，而验证数据在1000次重复中达到了92.8%的敏感性、89.5%的特异性和90.3%的准确率。阳性病例与晚期疾病（P < 0.001）、较大肿瘤（P = 0.002）、远处转移（P < 0.001）和疾病进展（P < 0.001）显著相关。对于监测治疗反应和肿瘤负荷，对治疗反应良好的患者甲基化水平降低，而在癌症进展或转移前的病例中甲基化水平升高。