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A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Nature Genetics volume 47, pages 1079–1084 (2015)Cite this article

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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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Figure 1: A pharmacogenetic association with susceptibility to ACT is situated in RARG.
Figure 2: Functional characterization of RARG Ser427Leu identifies impaired transcriptional regulation.

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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

  1. Ursula Amstutz & Ursula Amstutz

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

  2. Folefac Aminkeng, Amit P Bhavsar, Nada Jabado, Anelise Espirito Santo and Martine Nagy: These authors contributed equally to this work.

  3. Bruce C Carleton, Michael R Hayden, Colin J D Ross, Margaret Murray, Darlene Boliver, Marilyn Tiller and Carol-anne Osborne: These authors jointly supervised this work.

  4. Lisa Goodyear, Lynette Bowes, Norma Kean and Jack Hand: Deceased.

Authors and 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, Michael R Hayden, Colin J D Ross, Henk Visscher, Folefac Aminkeng, Fudan Miao, Michelle Higginson, Nasim Massah & Jong W Lee

  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, Michael R Hayden, Bruce C Carleton, Colin J D Ross, Stuart MacLeod, Shahrad R Rassekh, Folefac Aminkeng, Ursula Amstutz, Amit P Bhavsar, Yuling Li & Jong W Lee

  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, Bruce C Carleton, Colin J D Ross, Stuart MacLeod, Amit P Bhavsar & Yuling Li

  4. Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands

    Henk Visscher & 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 & 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 & 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 & 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, 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. Folefac Aminkeng
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  5. Yuling Li
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  6. Jong W Lee
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  7. Liam R Brunham
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Consortia

The Canadian Pharmacogenomics Network for Drug Safety Consortium

  • Michael R Hayden
  • , Bruce C Carleton
  • , Colin J D Ross
  • , Stuart MacLeod
  • , Anne Smith
  • , Claudette Hildebrand
  • , Reza Ghannadan
  • , Shahrad R Rassekh
  • , Henk Visscher
  • , Folefac Aminkeng
  • , Fudan Miao
  • , Michelle Higginson
  • , Nasim Massah
  • , Adrienne Borrie
  • , Ursula Amstutz
  • , Shevaun Hughes
  • , Kaitlyn Shaw
  • , Satvir Dhoot
  • , Amit P Bhavsar
  • , Yuling Li
  • , Jong W Lee
  • , Kaarina Kowalec
  • , Jessica Stortz
  • , Tessa Bendyshe-Walton
  • , Duncan Waltrip
  • , Rachel Bader
  • , Cheri Nijssen-Jordan
  • , David Johnson
  • , Linda Verbeek
  • , Rick Kaczowka
  • , Patti Stevenson
  • , Carnation Zhuwaki
  • , Paul Grundy
  • , Kent Stobart
  • , Bev Wilson
  • , Sunil Desai
  • , Maria Spavor
  • , Linda Churcher
  • , Terence Chow
  • , Kevin Hall
  • , Nick Honcharik
  • , Sara Israels
  • , Shanna Chan
  • , Byron Garnham
  • , Michelle Staub
  • , Geert 't Jong
  • , Michael J Rieder
  • , Becky Malkin
  • , Carol Portwine
  • , Amy Cranston
  • , 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
  • , Mariana Silva
  • , Stephanie Willing
  • , Régis Vaillancourt
  • , Donna Johnston
  • , Herpreet Mankoo
  • , Elaine Wong
  • , Brenda Wilson
  • , Lauren O'Connor
  • , Caleb Hui
  • , Cindy Yuen
  • , Jean-Francois Bussières
  • , Denis Lebel
  • , Pierre Barret
  • , Aurélie Clauson
  • , Eve Courbon
  • , Léna Cerruti
  • , Nada Jabado
  • , Anelise Espirito Santo
  • , Martine Nagy
  • , Margaret Murray
  • , Darlene Boliver
  • , Marilyn Tiller
  • , Carol-anne Osborne
  • , Lisa Goodyear
  • , Lynette Bowes
  • , Norma Kean
  •  & Jack Hand

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.

Corresponding author

Correspondence to Colin J D Ross.

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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).

Integrated supplementary information

Supplementary Figure 1 Study design.

Supplementary Figure 2 GWAS of anthracycline-induced cardiotoxicity in childhood cancer.

(a) Manhattan plot showing the observed distribution of –log10 (P values) against SNP chromosomal localization (GRCH37.p13). P values are for logistic regression analysis (additive model) with adjustment for age, cumulative dose, tumor type (ALL, Ewing’s sarcoma or rhabdomyosarcoma) and radiotherapy. Red line, P = 1.0 × 10–5 (ref.1). (b) Quantile-quantile plot. Quantile-quantile plot showing the distributions of observed –log10 (P values) plotted against expected –log10 (P values) (λGC = 1.021). Smaller P values than would be expected by chance were observed at the tail of the plot. λGC = 1.021 indicates no obvious population stratification.

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Supplementary Text and Figures

Supplementary Figures 1 and 2, and Supplementary Tables 1–7. (PDF 645 kb)

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Aminkeng, F., Bhavsar, A., Visscher, H. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47, 1079–1084 (2015). https://doi.org/10.1038/ng.3374

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