目的

分析脑源性无细胞DNA（brain-derived cell-free DNA，bd-cfDNA）对肺癌脑转移放射性脑损伤（radiation brain injury，RBI）的预测意义。

方法

选择2020 年3 月至2022 年3 月我院收治的晚期肺癌并发脑转移患者83 例为对象，放疗后发生RBI 33 例为观察组，未发生RBI 50 例为对照组。 放疗前后检测血浆中总cfDNA 水平，采用组织特异性甲基化模式溯源cfDNA。 应用多因素二元Logistic 和受试者工作特征（receiver operating characteristic，ROC）曲线分析bd-cfDNA 对RBI 的预测。

结果

观察组放疗后血小板淋巴细胞比值（platelet lymphocyte ratio，PLR） 256.00（226.50，289.00）和总靶体积（gross tumor volume，GTV） Dmax 5 032.10（4 936.25，5 125.35）高于对照组PLR 221.50（184.25，252.25）和GTV Dmax 4 938.50（4 833.40，5 032.93）（P＜0.05）。 两组放疗前cfDNA 差异无统计学意义（P＞0.05），两组放疗后少突胶质细胞来源ΔcfDNA、神经元来源ΔcfDNA、星形胶质细胞来源ΔcfDNA 及Δ 总bd-cfDNA 升高（P＜0.05），观察组放疗后少突胶质细胞来源ΔcfDNA12.07（0.28，2 706.43）copies/ml、神经元来源ΔcfDNA11.88（1.44，4 394.05）copies/ml、星形胶质细胞来源ΔcfDNA295.84（5.63，7 407.56）copies/ml 及Δ 总bd-cfDNA8433.13（348.75，29 514.12）copies/ml 高于对照组2.95（0.01，16.90）copies/ml、3.48（0.52，22.54）copies/ml、13.69（2.07，89.33）copies/ml、72.38（25.44，1 343.92）copies/ml（P＜0.001）。 观察组放疗前后少突胶质细胞来源ΔcfDNA19.80（0.25，3159.96）copies/ml、神经元来源ΔcfDNA19.61（0.48，4 646.08）copies/ml、星形胶质细胞来源ΔcfDNA262.05（1.62，8 298.91）copies/ml 及Δ 总bd-cfDNA 4 936.47（229.22，24 740.52）copies/ml 高于对照组0.65（-0.11，14.54）copies/ml、1.63（0.07，15.45）copies/ml、3.93（-2.25，77.83）copies/ml、34.71（0.57，433.65）copies/ml（P＜0.05）。 多因素二元Logistic 分析显示，放疗后Δ 总bd-cfDNA≥568.68 copies/ml 增加RBI 发生风险［HR：5.194（95%CI：1.760～15.326），P ＝0.003］。 ROC 曲线分析显示，放疗后Δ 总bd-cfDNA 预测RBI 的曲线下面积为0.782（95%CI：0.674 ～0.891）（P＜0.05）。

结论

放疗后bd-cfDNA 可预测肺癌脑转移RBI，具有临床意义。

Objective

To analyze the predictive value of brain-derived cell-free DNA （bd-cfDNA） for radiation brain injury （RBI） in patients with lung cancer brain metastases.

Methods

A total of 83 patients with advanced lung cancer complicated with brain metastasis admitted to our hospital from March 2020 to March 2022 were selected as the subjects，33 patients with RBI after brain radiotherapy were selected as the observation group，and 50 patients without RBI were selected as the control group.The total cfDNA levels in plasma were measured before and after radiotherapy，and the origin of cfDNA was traced using tissue-specific methylation patterns.Multivariate binary Logistic and receiver operating characteristic （ROC） curve were used to analyze the prediction of RBI by bd-cfDNA.

Results

After radiotherapy，PLR 256.00 （226.50，289.00）and GTV Dmax 5 032.10 （4 936.25，5 125.35） in observation group were higher than those in control group 252.25 （221.50，184.25） and GTV Dmax 4 938.50 （4 833.40，5 032.93） （P ＜0.05）.There was no significant difference in cfDNA between the two groups before radiotherapy （P＞0.05）.After radiotherapy，cfDNA from oligodendrocytes，cfDNA from neurons，cfDNA from astrocytes and total bd-cfDNA were increased between the two groups （P＜0.05）.In the observation group，after radiotherapy，the source of oligodendrocytes was 12.07 （0.28，2 706.43） copies/ml，the source of neurons was 11.88 （1.44，4 394.05） copies/ml，and the source of astrocytes was cfDNA295.84 （5.63，5.28，4 394.05） copies/ml and total bd-cfDNA 8 433.13（348.75，29 514.12） copies/ml were higher than those in the control group 2.95（0.01，16.90）copies/ml，3.48（0.52，22.54）copies/ml，13.69（2.07，89.33）copies/ml，72.38（25.44，1343.92）copies/ml （P＜0.001）.In the observation group before and after radiotherapy，oligodendrocyte sources were cfDNA19.80 （0.25，3 159.96） copies/ml，neuronal sources ΔcfDNA19.61 （0.48，4 646.08） copies/ml，astrocyte sources ΔcfDNA 262.05 （1.62，8 298.91） copies/ml and Δ total bd-cfDNA 4 936.47 （229.22，24 740.52） copies/ml were higher than that of the control group 0.65 （-0.11，14.54） copies/ml，1.63 （0.07，0.07） copies/ml.15.45）copies/ml，3.93 （-2.25，77.83） copies/ml，34.71 （0.57，433.65） copies/ml （P＜0.05）.Multivariate binary Logistic analysis showed that total bd-cfDNA≥568.68 copies/ml after radiotherapy increased the risk of RBI［HR： 5.194 （95%CI： 1.760-15.326）， P＝0.003］.ROC curve analysis showed that the area under the curve of total bd-cfDNA predicting RBI after radiotherapy was 0.782 （95%CI： 0.674-0.891）（P＜0.05）.

Conclusion

bd-cfDNA can predict RBI of lung cancer brain metastases after radiotherapy，which has clinical significance.