Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

Marije J. Klumpers, Ward De Witte, Giovanna Gattuso, Elisabetta Schiavello, Monica Terenziani, Maura Massimino, Corrie E.M. Gidding, Sita H. Vermeulen, Chantal M. Driessen, Carla M. van Herpen, Esther van Meerten, Henk Jan Guchelaar, Marieke J.H. Coenen, D. Maroeska W.M. Te Loo*

*Corresponding author for this work

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Abstract

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head–neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient −0.10 (95% confidence interval −0.13–−0.06), p-value 2.72 × 10−8). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study’s cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study’s results in independent cohorts is needed to confirm this novel association.

Original languageEnglish
Article number892
JournalJournal of Personalized Medicine
Volume12
Issue number6
DOIs
Publication statusPublished - 28 May 2022

Bibliographical note

Funding Information:
Funding: This work was funded by the Princess Máxima Center Foundation, Utrecht, the Netherlands (reference 02022016).

Funding Information:
Acknowledgments: We acknowledge Zazuli et al. (2021) for providing the requested summary statistics. We would like to acknowledge all the patients and parents who participated in this study. We acknowledge the contribution of Johanne M. Groothuismink (Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands) for her guidance on and assistance with the genotyping. This work is part of the research program, Computing Time National Computing Facilities Processing Round Pilots, 2018, under project number 17666, and is (partly) financed by the Dutch Research Council (NWO). This work was carried out using the Dutch national e-infrastructure with the support of SURF Cooperative.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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