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SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin

Affiliation
Department of Human Genetics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Hurkmans, Evelien G. E.;
Affiliation
Department of Pharmacology and Toxicology ,Radboud University Medical Center ,Nijmegen ,Netherlands
Koenderink, Jan B.;
Affiliation
Department of Pharmacology and Toxicology ,Radboud University Medical Center ,Nijmegen ,Netherlands
van den Heuvel, Jeroen J. M. W.;
Affiliation
Department of Medical Oncology ,Radboud University Medical Center ,Nijmegen ,Netherlands
Versleijen-Jonkers, Yvonne M. H.;
Affiliation
Department of Medical Oncology ,Radboud University Medical Center ,Nijmegen ,Netherlands
Hillebrandt-Roeffen, Melissa H. S.;
Affiliation
Department of Human Genetics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Groothuismink, Johanne M.;
Affiliation
Department of Human Genetics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Vos, Hanneke I.;
Affiliation
Department of Medical Oncology ,Radboud University Medical Center ,Nijmegen ,Netherlands
van der Graaf, Winette T. A.;
Affiliation
Department of Pathology ,Radboud University Medical Center ,Nijmegen ,Netherlands
Flucke, Uta;
Affiliation
Department of Pharmacology and Toxicology ,Radboud University Medical Center ,Nijmegen ,Netherlands
Muradjan, Grigor;
Affiliation
Department of Orthopedics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Schreuder, Hendrik W. B.;
Affiliation
Princess Maxima Center for Pediatric Oncology ,Utrecht ,Netherlands
Hagleitner, Melanie M.;
Affiliation
Department of Human Genetics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Brunner, Han G.;
Affiliation
Department of Medical Oncology ,Leiden University Medical Center ,Leiden ,Netherlands
Gelderblom, Hans;
Affiliation
Department of Pathology ,Leiden University Medical Center ,Leiden ,Netherlands
Cleton-Jansen, Anne-Marie;
Affiliation
Department of Clinical Pharmacy & Toxicology ,Leiden University Medical Center ,Leiden ,Netherlands
Guchelaar, Henk-Jan;
Affiliation
Department of Pediatrics ,Beatrix Children’s Hospital ,University Medical Center Groningen ,Groningen ,Netherlands
de Bont, Eveline S. J. M.;
Affiliation
Department of Clinical Pharmacy and Pharmacology ,University Medical Center Groningen ,Groningen ,Netherlands
Touw, Daan J.;
Affiliation
Department of Clinical Pharmacy and Pharmacology ,University Medical Center Groningen ,Groningen ,Netherlands
Nijhoff, G. Jan;
Affiliation
Department of Pediatrics ,Amsterdam University Medical Centers ,Emma Children’s Hospital ,Amsterdam ,Netherlands
Kremer, Leontien C. M.;
Affiliation
Department of Pediatrics ,Amsterdam University Medical Centers ,Emma Children’s Hospital ,Amsterdam ,Netherlands
Caron, Huib;
Affiliation
Pediatric & Adolescent Division ,University College London Hospitals NHS Foundation Trust ,London ,United Kingdom
Windsor, Rachael;
Affiliation
Department of Pediatrics ,Clínica Universidad de Navarra ,Solid Tumor Program ,CIMA ,Pamplona ,Spain
Patiño-García, Ana;
Affiliation
Human Genotyping Unit-CeGen ,Spanish National Cancer Research Centre (CNIO) ,Madrid ,Spain
González-Neira, Anna;
Affiliation
Children’s Cancer Research Unit ,The Children’s Hospital at Westmead ,Sydney ,NSW ,Australia
Saletta, Federica;
Affiliation
Cancer Centre for Children ,The Children’s Hospital at Westmead ,Sydney ,NSW ,Australia
McCowage, Geoff;
Affiliation
Cancer Centre for Children ,The Children’s Hospital at Westmead ,Sydney ,NSW ,Australia
Nagabushan, Sumanth;
Affiliation
Children’s Cancer Research Unit ,The Children’s Hospital at Westmead ,Sydney ,NSW ,Australia
Catchpoole, Daniel;
Affiliation
Department of Pediatrics ,Amalia Children’s Hospital ,Radboud University Medical Center ,Nijmegen ,Netherlands
te Loo, D. Maroeska W. M.;
Affiliation
Department of Human Genetics ,Radboud University Medical Center ,Nijmegen ,Netherlands
Coenen, Marieke J. H.

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.

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License Holder: Copyright © 2022 Hurkmans, Koenderink, van den Heuvel, Versleijen-Jonkers, Hillebrandt-Roeffen, Groothuismink, Vos, van der Graaf, Flucke, Muradjan, Schreuder, Hagleitner, Brunner, Gelderblom, Cleton-Jansen, Guchelaar, de Bont, Touw, Nijhoff, Kremer, Caron, Windsor, Patiño-García, González-Neira, Saletta, McCowage, Nagabushan, Catchpoole, te Loo and Coenen.

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