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. 2019 May 10;10(5):364.
doi: 10.3390/genes10050364.

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

Zulfan Zazuli  1   2   3 , Leila S Otten  4 , Britt I Drögemöller  5   6 , Mara Medeiros  7   8 , Jose G Monzon  9 , Galen E B Wright  10   11 , Christian K Kollmannsberger  12 , Philippe L Bedard  13 , Zhuo Chen  14 , Karen A Gelmon  15 , Nicole McGoldrick  16 , Abhijat Kitchlu  17 , Susanne J H Vijverberg  18 , Rosalinde Masereeuw  19 , Colin J D Ross  20   21 , Geoffrey Liu  22 , Bruce C Carleton  23   24 , Anke H Maitland-van der Zee  25
Affiliations

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

Zulfan Zazuli et al. Genes (Basel). .

Abstract

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.

Keywords: cisplatin; genetic polymorphisms; kidney injury; nephrotoxicity; pharmacogenetics.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

Figures

Figure 1
Figure 1
Flowchart of patient inclusion in statistical analyses.
See this image and copyright information in PMC

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