To identify DNA methylation related biomarkers in patients with breast cancer (BC).

A total of seven BC methylation studies including 1,438 BC patients or breast tissues were included in this study. An elastic net regularized Cox proportional hazards regression (CPH) model was used to build a multi-5′-C-phosphate-G-3′ methylation panel. The diagnosis and prognosis power of the panel was evaluated and validated using a Kaplan–Meier curve, univariate and multivariable CPH, subgroup analysis. A nomogram containing the panel was developed. The relationships between the panel-based methylation risk and the immune landscape and genomic metrics were investigated.

Sixty-eight CpG sites were significantly correlated with the overall survival (OS) of BC patients, and based on the result of penalized CPH, a 28-CpG site based multi CpG methylation panel was found. The prognosis and diagnosis role of the panel was validated in the discovery set, validation set, and six independent cohorts, which indicated that higher methylation risk was associated with poor OS, and the panel outperformed currently available biomarkers and remained an independent factor after adjusting for other clinical features. The methylation risk was negatively correlated with innated and adaptive immune cells, and positively correlated with total mutation load, SCNA, and MATH.

We validated a multi CpG methylation panel that could independently predict the OS of BC patients. The Th2-mediated tumor promotion effect—suppression of innate and adaptive immunity—participated in the progression of high-risk BC. Patients with high methylation risk were associated with tumor heterogeneity and poor survival.

鉴定乳腺癌 (BC) 患者的 DNA 甲基化相关生物标志物。

本研究共纳入 7 项 BC 甲基化研究，包括 1,438 名 BC 患者或乳腺组织。使用弹性网正则化 Cox 比例风险回归 (CPH) 模型构建多 5'-C-磷酸盐-G-3' 甲基化面板。使用 Kaplan-Meier 曲线、单变量和多变量 CPH、亚组分析评估和验证小组的诊断和预后能力。开发了包含面板的列线图。研究了基于小组的甲基化风险与免疫景观和基因组指标之间的关系。

68 个 CpG 位点与 BC 患者的总生存期 (OS) 显着相关，并且基于惩罚 CPH 的结果，发现了一个基于 28-CpG 位点的多 CpG 甲基化面板。该小组的预后和诊断作用在发现集、验证集和六个独立队列中得到验证，这表明较高的甲基化风险与较差的 OS 相关，并且该小组的表现优于目前可用的生物标志物，并且在调整后仍然是一个独立因素其他临床特征。甲基化风险与先天性和适应性免疫细胞呈负相关，与总突变负荷、SCNA 和 MATH 呈正相关。

我们验证了可以独立预测 BC 患者 OS 的多 CpG 甲基化面板。Th2 介导的肿瘤促进作用——抑制先天性和适应性免疫——参与了高危 BC 的进展。甲基化风险高的患者与肿瘤异质性和生存率低有关。