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

doi:10.3390/jpm12060892

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

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	892
Journal	Journal of Personalized Medicine
Volume	12
Issue number	6
DOIs	https://doi.org/10.3390/jpm12060892
Publication status	Published - 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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Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney InjuryFinal published version, 1.03 MBLicence: CC BY

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Klumpers, M. J., De Witte, W., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., Gidding, C. E. M., Vermeulen, S. H., Driessen, C. M., van Herpen, C. M., van Meerten, E., Guchelaar, H. J., Coenen, M. J. H., & Te Loo, D. M. W. M. (2022). Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury. Journal of Personalized Medicine, 12(6), Article 892. https://doi.org/10.3390/jpm12060892

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

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{\textquoteright}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{\textquoteright}s results in independent cohorts is needed to confirm this novel association.",

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

note = "Funding Information: Funding: This work was funded by the Princess M{\'a}xima 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: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = may,

day = "28",

doi = "10.3390/jpm12060892",

language = "English",

volume = "12",

journal = "Journal of Personalized Medicine",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "6",

}

Klumpers, MJ, De Witte, W, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, Gidding, CEM, Vermeulen, SH, Driessen, CM, van Herpen, CM, van Meerten, E, Guchelaar, HJ, Coenen, MJH & Te Loo, DMWM 2022, 'Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury', Journal of Personalized Medicine, vol. 12, no. 6, 892. https://doi.org/10.3390/jpm12060892

TY - JOUR

T1 - Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

AU - Klumpers, Marije J.

AU - De Witte, Ward

AU - Gattuso, Giovanna

AU - Schiavello, Elisabetta

AU - Terenziani, Monica

AU - Massimino, Maura

AU - Gidding, Corrie E.M.

AU - Vermeulen, Sita H.

AU - Driessen, Chantal M.

AU - van Herpen, Carla M.

AU - van Meerten, Esther

AU - Guchelaar, Henk Jan

AU - Coenen, Marieke J.H.

AU - Te Loo, D. Maroeska W.M.

N1 - 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.

PY - 2022/5/28

Y1 - 2022/5/28

N2 - 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.

AB - 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.

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U2 - 10.3390/jpm12060892

DO - 10.3390/jpm12060892

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

Abstract

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