Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200433, China.
Department of Radiotherapy, Shanghai Fourth Peoples Hospital, School of Medicine, Tongji University, No. 1878, Sichuan North Road, Shanghai, 200081, China.
Anal Chim Acta. 2024 Nov 22;1330:343202. doi: 10.1016/j.aca.2024.343202. Epub 2024 Sep 11.
Esophageal adenocarcinoma is a leading cause of mortality worldwide. New evidence indicates that liquid-liquid phase separation is related to malignancies. The current study aims at exploring the functions of liquid-liquid phase separation within esophageal adenocarcinoma. Patients within the TCGA dataset were classified using liquid-liquid phase separation-related genes. Significantly differentially expressed genes and prognostic factors for overall survival have been screened by Cox regression. Based on the liquid-liquid phase separation score, the construction of a prognostic model and liquid-liquid phase separation signature was constructed. Tumor mutation burden and drug sensitivity were analyzed in two groups: high liquid-liquid phase separation scores, and low liquid-liquid phase separation scores. According to liquid-liquid phase separation, some small-molecule compounds targeting esophageal adenocarcinoma were screened. The results were verified in vitro with an external cohort.
87 samples are involved, and 61 liquid-liquid phase separation-related genes may influence esophageal adenocarcinoma by changing DNA conformation and metabolism. Meanwhile, based on a high liquid-liquid phase separation score and low score group including 43 patients, it is found that the result significantly lowered the 5-year overall survival to 32.6 %, compared to 64.8 % in the low-score group of 44 patients with p < 0.001. The high score group had an average TIDE score of 0.27 versus 0.14 in the low-score group, with p = 0.003. The median tumor mutation burden was 9.1 mutations/Mb in the high-score group versus 6.4 mutations/Mb in the low-score group, with p = 0.011. The predictive model worked very well, with area under the curve values of 0.82, 0.79, and 0.76 for 1-, 3-, and 5-year survival, respectively. Liquid-liquid phase separation has been validated as an effective prognostic biomarker and drug sensitivity predictor.
Liquid-liquid phase separation is potentially implicated in esophageal adenocarcinoma and works as a prognostic biomarker assessment of vulnerability to LLPS, which could help develop individualized therapies by showing how one is situated about various medications where responses vary across the body.
食管腺癌是全球主要的死亡原因。新证据表明液-液相分离与恶性肿瘤有关。本研究旨在探讨液-液相分离在食管腺癌中的作用。利用液-液相分离相关基因对 TCGA 数据集患者进行分类。通过 Cox 回归筛选出总生存差异表达基因和预后因素。根据液-液相分离评分，构建预后模型和液-液相分离特征。分析两组肿瘤突变负担和药物敏感性：高液-液相分离评分组和低液-液相分离评分组。根据液-液相分离，筛选了针对食管腺癌的一些小分子化合物。并在外部队列中进行了验证。
涉及 87 例样本，61 个液-液相分离相关基因可能通过改变 DNA 构象和代谢影响食管腺癌。同时，根据高液-液相分离评分和低评分组（43 例），发现高评分组 5 年总生存率显著降低至 32.6%，而低评分组（44 例）为 64.8%，p<0.001。高评分组平均 TIDE 评分（0.27）高于低评分组（0.14），p=0.003。高评分组的肿瘤突变负担中位数为 9.1 突变/Mb，低评分组为 6.4 突变/Mb，p=0.011。预测模型效果很好，1 年、3 年和 5 年生存率的 AUC 值分别为 0.82、0.79 和 0.76。液-液相分离已被验证为有效的预后生物标志物和药物敏感性预测因子。
液-液相分离可能与食管腺癌有关，可作为液-液相分离易感性的预后生物标志物评估，这有助于通过显示个体对各种药物的敏感性来制定个体化治疗方案，因为药物的反应在全身范围内存在差异。
