SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin
Frontiers in Pharmacology, vol. 13, pp. 1042989
Abstract
Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06–0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
Authors 30
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Orthopedics, Radboud University Medical Center, Nijmegen, Netherlands
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Affiliation as printed
Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands
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University Medical Center Groningen · Beatrix Kinderziekenhuis
Affiliation as printed
Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Department of Pediatrics, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Department of Pediatrics, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, Netherlands
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University College London Hospitals NHS Foundation Trust
Affiliation as printed
Pediatric & Adolescent Division, University College London Hospitals NHS Foundation Trust, London, United Kingdom
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Clinica Universidad de Navarra · Centro de Investigación Médica Aplicada
Affiliation as printed
Department of Pediatrics, Clínica Universidad de Navarra, Solid Tumor Program, CIMA, Pamplona, Spain
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Spanish National Cancer Research Centre
Affiliation as printed
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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Children's Hospital at Westmead
Affiliation as printed
Children's Cancer Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia
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Children's Hospital at Westmead
Affiliation as printed
Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, NSW, Australia
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The University of Sydney · Children's Hospital at Westmead
Affiliation as printed
Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, NSW, Australia
Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW, Australia
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Children's Hospital at Westmead
Affiliation as printed
Children's Cancer Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia
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Radboud University Nijmegen · Radboud University Medical Center · Amalia Kinderziekenhuis
Affiliation as printed
Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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