Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with or without BM (n = 346). LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, which was integrated with clinical factors to provide comprehensive patient-specific BM risk probabilities in a nomogram. Additionally, immune and cell interaction gene sets were differentially methylated at promoters in BM versus paired primary LUAD and had aligning dysregulation in the proteome. Immune cells were differentially abundant in BM versus LUAD. Finally, liquid biomarkers identified from methylated cell-free DNA sequenced in plasma were used to generate and validate accurate classifiers for early BM detection. Overall, LUAD methylomes can be leveraged to predict and noninvasively identify BM, moving toward improved patient outcomes with personalized treatment.

脑转移瘤 （BMs） 是最常见也是最致命的脑肿瘤之一。目前，没有可靠的原发性癌症 BM 发展的预测因子，这限制了早期干预。肺腺癌 （LUAD） 是最常见的 BM 来源，在这里我们从一大群伴或不伴 BM 的 LUAD 患者那里获得了 402 份肿瘤和血浆样本 （n = 346）。评估 LUAD DNA 甲基化特征以构建和验证从 LUAD 预测 BM 发展的准确模型，该模型与临床因素相结合，在列线图中提供全面的患者特异性 BM 风险概率。此外，免疫和细胞相互作用基因集在 BM 与配对的初级 LUAD 的启动子处发生差异甲基化，并且在蛋白质组中具有对齐失调。BM 与 LUAD 中的免疫细胞丰富度差异。最后，使用从血浆中测序的甲基化游离 DNA 中鉴定的液体生物标志物来生成和验证用于早期 BM 检测的准确分类器。总体而言，LUAD 甲基化组可用于预测和无创识别 BM，通过个性化治疗改善患者预后。