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Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients.
Xiao, Qingyang; Zhou, Yitian; Winter, Stefan; Büttner, Florian; Schaeffeler, Elke; Schwab, Matthias; Lauschke, Volker M.
Afiliação
  • Xiao Q; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • Zhou Y; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • Winter S; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Tuebingen, Germany.
  • Büttner F; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Tuebingen, Germany.
  • Schaeffeler E; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Tuebingen, Germany.
  • Schwab M; iFIT Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Tuebingen, Germany.
  • Lauschke VM; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Tuebingen, Germany.
Int J Cancer ; 146(9): 2475-2487, 2020 05 01.
Article em En | MEDLINE | ID: mdl-32010961
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Biomarcadores Tumorais / Mutação em Linhagem Germinativa / Resistencia a Medicamentos Antineoplásicos / Proteínas Associadas à Resistência a Múltiplos Medicamentos Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Biomarcadores Tumorais / Mutação em Linhagem Germinativa / Resistencia a Medicamentos Antineoplásicos / Proteínas Associadas à Resistência a Múltiplos Medicamentos Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article