The Association of R-Loop Binding Proteins Subtypes with CIN Implicates Therapeutic Strategies in Colorectal Cancer.
The Association of R-Loop Binding Proteins Subtypes with CIN Implicates Therapeutic Strategies in Colorectal Cancer.
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R 环结合蛋白亚型与 CIN 的关联暗示结直肠癌的治疗策略
作者：
R-Loop由R-Loop结合蛋白（RLBP）精细调控，在维持基因组稳定性方面发挥关键作用。通过整合蛋白基因组学分析，我们确定了两个RLBP亚型在结直肠癌（CRC）中具有明显的预后和治疗差异。以RLBPs高表达为特征的EGFR-I（CI）与染色体不稳定性（CIN）、更好的预后以及对靶向基因组完整性和EGFR的药物的敏感性相关。以RLBP低表达为特征的CII与粘液腺癌、右半结肠癌和预后不良相关。CII富含高炎症信号通路和淋巴细胞浸润，提示靶向炎症和免疫反应的药物具有潜在的应用价值。我们的研究可能有助于CRC的精确治疗。摘要染色体不稳定性（CIN）占结直肠癌患者的65%~ 70%，在肿瘤进展中起重要作用。然而，与这些患者相关的分子特征和治疗策略仍然存在争议。R环结合蛋白（RLBP）在转录和复制中发挥重要作用。在这里，整合的结直肠癌蛋白基因组学分析确定了两个RLBP亚型与不同的肿瘤相关。以RLBP高表达为代表的簇I（CI）与CIN表型相关。而RLBPs低表达且预后最差的群集II（CII）由高比例的粘液腺癌或右半结肠癌患者组成。分子特征分析显示，CI是一条高度炎症信号通路，其RNA加工、核糖体合成活跃，DNA损伤修复异常，淋巴细胞浸润丰富。此外，我们还发现了42种肿瘤相关RLBPs蛋白。在细胞和类器官模型中，具有高表达肿瘤相关蛋白的CI对靶向基因组完整性和EGFR的药物敏感。因此，我们的研究揭示了CIN表型与RLBP的重要分子关联，并且还为进一步探索RLBP在癌症进展和治疗应用中的功能提供了有力的资源。
Simple Summary R-Loops, finely regulated by R-Loop binding proteins (RLBPs), play pivotal roles in maintaining genomic stability. By integrated proteogenomic analysis, we identified two RLBPs subtypes with distinct prognostic and therapeutic differences in colorectal cancer (CRC). Cluster-I (CI), characterized by high expression of RLBPs, was associated with chromosomal instability (CIN), better prognosis, and sensitivity to drugs targeting genome integrity and EGFR. Cluster-II (CII), characterized by low expression of RLBPs, was associated with mucinous adenocarcinoma, right-sided colon cancer, and poor prognosis. High inflammatory signaling pathway and lymphocyte infiltration enriched in CII, indicating potential application of drugs targeting inflammatory and immune response. Our research might be helpful for the precision treatment of CRC. Abstract Chromosomal instability (CIN) covers approximately 65 to 70% of colorectal cancer patients and plays an essential role in cancer progression. However, the molecular features and therapeutic strategies related to those patients are still controversial. R-loop binding proteins (RLBPs) exert significant roles in transcription and replication. Here, integrative colorectal cancer proteogenomic analysis identified two RLBPs subtypes correlated with distinct prognoses. Cluster I (CI), represented by high expression of RLBPs, was associated with the CIN phenotype. While Cluster II (CII) with the worst prognosis and low expression of RLBPs was composed of a high percentage of patients with mucinous adenocarcinoma or right-sided colon cancer. The molecular feature analysis revealed that the active RNA processing, ribosome synthesis, and aberrant DNA damage repair were shown in CI, a high inflammatory signaling pathway, and lymphocyte infiltration was enriched in CII. In addition, we revealed 42 tumor-associated RLBPs proteins. The CI with high expression of tumor-associated proteins was sensitive to drugs targeting genome integrity and EGFR in both cell and organoid models. Thus, our study unveils a significant molecular association of the CIN phenotype with RLBPs, and also provides a powerful resource for further functional exploration of RLBPs in cancer progression and therapeutic application.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
16.6
作者：
Day TA;Layer JV;Cleary JP;Guha S;Stevenson KE;Tivey T;Kim S;Schinzel AC;Izzo F;Doench J;Root DE;Hahn WC;Price BD;Weinstock DM
通讯作者：
Weinstock DM
影响因子：
64.5
作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
64.8
作者：
Gorthi A;Romero JC;Loranc E;Cao L;Lawrence LA;Goodale E;Iniguez AB;Bernard X;Masamsetti VP;Roston S;Lawlor ER;Toretsky JA;Stegmaier K;Lessnick SL;Chen Y;Bishop AJR
通讯作者：
Bishop AJR