Abstract

Anthracyclines are used in over 50% of childhood cancer treatment protocols1, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively2,3. Candidate gene studies have reported genetic associations with ACT4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained12,13. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10−8, odds ratio (95% confidence interval) = 4.7 (2.7–8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

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Acknowledgements

We acknowledge the participation of all the patients and families who took part in this study across Canada, the Netherlands and the United States. This work was supported by the Canadian Institutes of Health Research (CIHR; FRN-88362 to B.C.C., M.R.H. and C.J.D.R.), the CIHR Drug Safety and Effectiveness Network (FRN-117588 to B.C.C. and C.J.D.R.), the US National Institutes of Health (1R21HL123655-01 and HL123655 to D.B., B.C.C. and C.J.D.R.), a Stanford Comprehensive Cancer Center Translation Research Grant (to D.B.), the Child & Family Research Institute (Vancouver, British Columbia, Canada; Bertram Hoffmeister Postdoctoral Fellowship Award for F.A.), the Michael Smith Foundation for Health Research (Postdoctoral Fellowship Award for F.A.), the CIHR Training Program in Bridging Scientific Domains for Drug Safety and Effectiveness–DSECT program (Postdoctoral Fellowship Award for F.A.), the Canada Foundation for Innovation, Genome British Columbia and the Provincial Health Service Authority. Additional funding was provided by the Child & Family Research Institute (Vancouver, British Columbia, Canada), the Faculty of Medicine of the University of British Columbia, the Canadian Gene Cure Foundation, the C17 Research Network and the Childhood Cancer Foundation–Candlelighters Canada.

Author information

Author notes

    • Ursula Amstutz

    Present address: Institute of Clinical Chemistry, Inselspital Bern University Hospital, and University of Bern, Bern, Switzerland.

    • Folefac Aminkeng
    •  & Amit P Bhavsar

    These authors contributed equally to this work.

    • Bruce C Carleton
    • , Michael R Hayden
    •  & Colin J D Ross

    These authors jointly supervised this work.

    • Jack Hand

    Deceased.

Affiliations

  1. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Folefac Aminkeng
    • , Henk Visscher
    • , Jong W Lee
    • , Michael R Hayden
    • , Colin J D Ross
    • , Fudan Miao
    • , Michelle Higginson
    •  & Nasim Massah
  2. Child and Family Research Institute, Vancouver, British Columbia, Canada.

    • Folefac Aminkeng
    • , Amit P Bhavsar
    • , Shahrad R Rassekh
    • , Yuling Li
    • , Jong W Lee
    • , Ursula Amstutz
    • , Bruce C Carleton
    • , Michael R Hayden
    • , Colin J D Ross
    •  & Stuart MacLeod
  3. Department of Pediatrics, Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Amit P Bhavsar
    • , Yuling Li
    • , Ursula Amstutz
    • , Bruce C Carleton
    • , Colin J D Ross
    •  & Stuart MacLeod
  4. Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Henk Visscher
  5. Department of Pediatrics, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplantation, University of British Columbia, Vancouver, British Columbia, Canada.

    • Shahrad R Rassekh
  6. Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore.

    • Liam R Brunham
    •  & Michael R Hayden
  7. Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.

    • Huib N Caron
    • , Elvira C van Dalen
    • , Leontien C Kremer
    •  & Helena J van der Pal
  8. Department of Medical Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands.

    • Helena J van der Pal
  9. Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.

    • Michael J Rieder
  10. Division of Pediatric Cardiology, Stanford University, Palo Alto, California, USA.

    • Daniel Bernstein
  11. Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.

    • Bruce C Carleton
    • , Colin J D Ross
    • , Stuart MacLeod
    • , Anne Smith
    • , Claudette Hildebrand
    • , Reza Ghannadan
    • , Adrienne Borrie
    • , Shevaun Hughes
    • , Kaitlyn Shaw
    • , Satvir Dhoot
    • , Kaarina Kowalec
    • , Jessica Stortz
    • , Tessa Bendyshe-Walton
    • , Duncan Waltrip
    •  & Rachel Bader
  12. Alberta Children's Hospital, Calgary, Alberta, Canada.

    • Cheri Nijssen-Jordan
    • , David Johnson
    • , Linda Verbeek
    • , Rick Kaczowka
    • , Patti Stevenson
    •  & Carnation Zhuwaki
  13. Stollery Children's Hospital, Edmonton, Alberta, Canada.

    • Paul Grundy
    • , Kent Stobart
    • , Bev Wilson
    • , Sunil Desai
    • , Maria Spavor
    • , Linda Churcher
    •  & Terence Chow
  14. Winnipeg Health Sciences Centre, Winnipeg, Manitoba, Canada.

    • Kevin Hall
    • , Nick Honcharik
    • , Sara Israels
    • , Shanna Chan
    • , Byron Garnham
    • , Michelle Staub
    •  & Geert 't Jong
  15. London Health Sciences Centre, London, Ontario, Canada.

    • Becky Malkin
  16. McMaster Children's Hospital, Hamilton, Ontario, Canada.

    • Carol Portwine
    •  & Amy Cranston
  17. Hospital for Sick Children, Toronto, Ontario, Canada.

    • Gideon Koren
    • , Shinya Ito
    • , Paul Nathan
    • , Mark Greenberg
    • , Facundo Garcia Bournissen
    • , Miho Inoue
    • , Sachi Sakaguchi
    • , Toshihiro Tanaka
    • , Hisaki Fujii
    • , Mina Ogawa
    • , Ryoko Ingram
    • , Taro Kamiya
    • , Smita Karande
    •  & Sholeh Ghayoori
  18. Kingston General Hospital, Kingston, Ontario, Canada.

    • Mariana Silva
    •  & Stephanie Willing
  19. Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

    • Régis Vaillancourt
    • , Donna Johnston
    • , Herpreet Mankoo
    • , Elaine Wong
    • , Brenda Wilson
    • , Lauren O'Connor
    • , Caleb Hui
    •  & Cindy Yuen
  20. CHU Sainte-Justine, Montreal, Quebec, Canada.

    • Jean-Francois Bussières
    • , Denis Lebel
    • , Pierre Barret
    • , Aurélie Clauson
    • , Eve Courbon
    •  & Léna Cerruti
  21. McGill University Health Centre–Montréal Children's Hospital, Montreal, Quebec, Canada.

    • Nada Jabado
    • , Anelise Espirito Santo
    •  & Martine Nagy
  22. IWK Health Centre, Halifax, Nova Scotia, Canada.

    • Margaret Murray
    • , Darlene Boliver
    • , Marilyn Tiller
    •  & Carol-anne Osborne
  23. Janeway Children's Hospital, St. John's, Newfoundland, Canada.

    • Lisa Goodyear
    • , Lynette Bowes
    • , Norma Kean
    •  & Jack Hand

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  1. The Canadian Pharmacogenomics Network for Drug Safety Consortium

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Contributions

B.C.C., M.R.H. and C.J.D.R. conceived and supervised the study. F.A., H.V., S.R.R., H.N.C., E.C.v.D., L.C.K., H.J.v.d.P., D.B., C.J.D.R., B.C.C. and the CPNDS Consortium enrolled the patients and collected and interpreted clinical data. F.A. conceived the statistical analyses, and F.A., H.V., J.W.L., A.P.B. and C.J.D.R. performed the statistical analyses. A.P.B. conceived the experiments, and A.P.B. and Y.L. performed the experiments. F.A., A.P.B., H.V., S.R.R., J.W.L., L.R.B., U.A., H.N.C., L.C.K., E.C.v.D., H.J.v.d.P., M.J.R., D.B., B.C.C., M.R.H. and C.J.D.R. analyzed and interpreted the data. All authors contributed to the writing, review and approval of the manuscript.

Competing interests

M.R.H., B.C.C., C.J.D.R., F.A., H.V. and A.P.B. have filed provisional patents based on the results of this work (US provisional patents 62/077,702 and 62/135,351).

Corresponding author

Correspondence to Colin J D Ross.

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DOI

https://doi.org/10.1038/ng.3374

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