Effect of ABC transporter expression and mutational status on survival rates of cancer patients - 28/10/20
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Highlights |
• | Overexpression of ABC transporters was associated with lower survival rates for various cancer types. |
• | Many of these identified associations have not been reported before. |
• | Three transmembrane domains (TM3, TM8 and TM9) of ABCB1 showed the highest mutation frequencies. |
• | Irinotecan, laniquidar and elacridar bound to P-glycoprotein independent of the mutation status. |
• | Truncated ABC transporters mutations shed light on a novel tumor-specific therapy strategy. |
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Abbreviations : ABC, BCRP, MDR, MRP
Keywords : ABC transporters, Cancer, Multidrug resistance, P-glycoprotein, Prognostic factor, Survival analysis
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Vol 131
Article 110718- novembre 2020 Retour au numéro
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