Identification of the origin of brain metastases based on the relative methylation orderings of CpG sites

Accurate diagnosis of the origin of brain metastases (BMs) is crucial for tailoring an effective therapy to improve patients’ prognosis. BMs of unknown origin account for approximately 2–14% of patients with BMs. Hence, the aim of this study was to identify the original cancer type of BMs based on their DNA methylation profiles. The DNA methylation profiles of glioma (GM), BM, and seven other types of primary cancers were collected. In comparison with GM, the reversal CpG site pairs were identified for each of the seven other types of primary cancers based on the within-sample relative methylation orderings (RMOs) of the CpG sites. Then, using the reversal CpG site pairs, GMs were distinguished from BMs and the seven other types of primary cancers. All 61 of the GM samples were correctly identified as GM. The cancer type was also identified for the non-GM samples. For the seven other types of primary cancers, greater than 93% of samples of each cancer type were correctly identified as their corresponding cancer type, except for breast cancer, which had an 88% accuracy. For 133 BM samples, 132 BM samples were identified as non-GM, and 95% of the 133 BM samples were correctly classified into their corresponding original cancer types. The RMO-based method can accurately identify the origin of BMs, which is important for precision treatment.准确诊断脑转移瘤（brain metastases, BMs）的原发灶，对于制定个体化有效治疗方案以改善患者预后至关重要。约2%~14%的脑转移瘤患者存在原发灶不明的情况。因此本研究旨在基于肿瘤的DNA甲基化谱，识别脑转移瘤的原发癌类型。本研究收集了胶质瘤（glioma, GM）、脑转移瘤以及另外7种原发性癌症的DNA甲基化谱。相较于胶质瘤，基于样本内CpG位点的相对甲基化排序（relative methylation orderings, RMOs），为其余7种原发性癌症分别鉴定出反向CpG位点对。随后利用该反向CpG位点对，可区分胶质瘤与脑转移瘤及其余7种原发性癌症。全部61例胶质瘤样本均被准确识别为胶质瘤。同时可对非胶质瘤样本进行癌型鉴定：除乳腺癌的识别准确率为88%外，其余7种原发性癌症的样本识别准确率均高于93%。针对133例脑转移瘤样本，其中132例被判定为非胶质瘤，且133例样本中有95%被准确归类至对应的原发癌类型。本研究基于相对甲基化排序的方法可精准识别脑转移瘤的原发灶，这对肿瘤精准治疗具有重要意义。