Germline variant burden in multidrug resistance transporters is a therapy‐specific predictor of survival in breast cancer patients. Issue 9 (17th February 2020)

• Record Type: Journal Article
• Authors: Xiao, Qingyang; Zhou, Yitian; Winter, Stefan; Büttner, Florian; Schaeffeler, Elke; Schwab, Matthias; Lauschke, Volker M.
• Is Part Of: International journal of cancer. Volume 146:Issue 9(2020)
• Page Start: 2475
• Page End: 2487
• Publication Date: 2020-02-17
• Subjects: multidrug resistance -- genetic variability -- personalized medicine -- population‐specificity -- rare variants -- variant frequency -- drug transport -- chemotherapy -- renal cancer -- breast cancer -- liver cancer; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32898
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Multidrug resistance due to facilitated drug efflux mediated by ATP‐binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease‐specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug‐specific for subgroups treated with the MRP1 substrates cyclophosphamide (log‐rank p = 0.0011) and doxorubicin (log‐rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log‐rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine. Abstract : What's new? Chemotherapy resistance is due in large part to ATP‐binding cassette (ABC) transporters, which actively remove drugs from cells. Multiple genetic variants, however, can alter ABC transporter activity, often modifying therapeutic responses. In this study, germline mutational burden in the multidrug resistance transporter ABCC1 ( MRP1 ) strongly predicted survival in breast cancer patients treated with the MRP1 substrates cyclophosphamide and doxorubicin. Structural analyses of mutated transporters revealed changes in protein stability and substrate binding. The findings delineate a role for high ABCC1 variant burden in driving chemoresistance in breast cancer patients and highlight the value of germline sequencing for predicting therapeutic response.