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Open AccessArticle

Outcome Definition Influences the Relationship between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients

1
Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
2
Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia
3
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3512 JE Utrecht, The Netherlands
4
British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
5
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada
6
Nephrology Research Unit, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
7
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
8
Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB T2N 4N2, Canada
9
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
10
BC Cancer Agency and University of British Columbia, Vancouver, BC V6T 1Z4, Canada
11
Princess Margaret Cancer Centre and University of Toronto, Toronto, ON M5S, Canada
12
Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre-University Health Network and University of Toronto, Toronto, ON M5S, Canada
13
Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, BC V6H 3N1, Canada
14
Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON M5S, Canada
15
Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(5), 364; https://doi.org/10.3390/genes10050364
Received: 16 April 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
(This article belongs to the Special Issue Pharmacogenomics and Personalized Medicine)
Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed. View Full-Text
Keywords: pharmacogenetics; cisplatin; nephrotoxicity; kidney injury; genetic polymorphisms pharmacogenetics; cisplatin; nephrotoxicity; kidney injury; genetic polymorphisms
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Zazuli, Z.; Otten, L.S.; Drögemöller, B.I.; Medeiros, M.; Monzon, J.G.; Wright, G.E.B.; Kollmannsberger, C.K.; Bedard, P.L.; Chen, Z.; Gelmon, K.A.; McGoldrick, N.; Kitchlu, A.; Vijverberg, S.J.H.; Masereeuw, R.; Ross, C.J.D.; Liu, G.; Carleton, B.C.; Maitland-van der Zee, A.H. Outcome Definition Influences the Relationship between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients. Genes 2019, 10, 364.

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