Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
Department of Medicine (Hematology, Oncology, and Pneumology), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Biomed Pharmacother. 2020 Nov;131:110718. doi: 10.1016/j.biopha.2020.110718. Epub 2020 Sep 12.
ATP-binding cassette (ABC) transporters mediate multidrug resistance in cancer. In contrast to DNA single nucleotide polymorphisms in normal tissues, the role of mutations in tumors is unknown. Furthermore, the significance of their expression for prediction of chemoresistance and survival prognosis is still under debate. We investigated 18 tumors by RNA-sequencing. The mutation rate varied from 27,507 to 300885. In ABCB1, three hotspots with novel mutations were in transmembrane domains 3, 8, and 9. We also mined the cBioPortal database with 11,814 patients from 23 different tumor entities. We performed Kaplan-Meier survival analyses to investigate the effect of ABC transporter expression on survival rates of cancer patients. Novel mutations were also found in ABCA2, ABCA3, ABCB2, ABCB5, ABCC1-6, and ABCG2. Mining the cBioPortal database with 11,814 patients from 23 different tumor entities validated our results. Missense and in-frame mutations led to altered binding of anticancer drugs in molecular docking approaches. The ABCB1 nonsense mutation Q856* led to a truncated P-glycoprotein, which may sensitize tumors to anticancer drugs. The search for ABC transporter nonsense mutations represents a novel approach for precision medicine.. Low ABCB1 mRNA expression correlated with significantly longer survival in ovarian or kidney cancer and thymoma. In cancers of breast, kidney or lung, ABC transporter expression correlated with different tumor stages and human populations as further parameters to refine strategies for more individualized chemotherapy.
三磷酸腺苷结合盒（ABC）转运蛋白介导癌症的多药耐药性。与正常组织中的 DNA 单核苷酸多态性不同，肿瘤突变的作用尚不清楚。此外，其表达对预测化疗耐药性和生存预后的意义仍存在争议。我们通过 RNA 测序研究了 18 个肿瘤。突变率从 27507 到 300885 不等。在 ABCB1 中，三个新突变热点位于跨膜域 3、8 和 9。我们还挖掘了来自 23 种不同肿瘤实体的 11814 名患者的 cBioPortal 数据库。我们进行了 Kaplan-Meier 生存分析，以研究 ABC 转运蛋白表达对癌症患者生存率的影响。还在 ABCA2、ABCA3、ABCB2、ABCB5、ABCC1-6 和 ABCG2 中发现了新的突变。挖掘来自 23 种不同肿瘤实体的 11814 名患者的 cBioPortal 数据库验证了我们的结果。错义和框移突变导致在分子对接方法中抗癌药物的结合发生改变。ABCB1 无义突变 Q856*导致 P-糖蛋白截断，这可能使肿瘤对抗癌药物敏感。寻找 ABC 转运蛋白无义突变代表了精准医学的一种新方法。。卵巢癌或肾癌和胸腺瘤中 ABCB1 mRNA 表达较低与生存时间显著延长相关。在乳腺癌、肾癌或肺癌中，ABC 转运蛋白的表达与不同的肿瘤分期和人群相关，这些参数可进一步细化更个体化化疗的策略。
