TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

A. J.M. Meijer; F. A. Diepstraten; T. Langer; L. Broer; I. K. Domingo; E. Clemens; A. G. Uitterlinden; A. C.H. de Vries; M. van Grotel; W. P. Vermeij; R. A. Ozinga; H. Binder; J. Byrne; E. van Dulmen-den Broeder; M. L. Garrè; D. Grabow; P. Kaatsch; M. Kaiser; L. Kenborg; J. F. Winther; C. Rechnitzer; H. Hasle; T. Kepak; K. Kepakova; W. J.E. Tissing; A.L.F. (Anne-Lotte) van der Kooi; L. C.M. Kremer; J. Kruseova; S. M.F. Pluijm; C. E. Kuehni; H. J.H. van der Pal; R. Parfitt; C. Spix; A. Tillmanns; D. Deuster; P. Matulat; G. Calaminus; A. E. Hoetink; S. Elsner; J. Gebauer; H. Lackner; R. Haupt; C. Blattmann; S. J.C.M.M. Neggers; Sharad R. Rassekh; G.E.B. Wright; B. Brooks; A. P. Nagtegaal; B.I. Drögemöller; C.J.D. Ross; A.P. Bhavsar; A.G.  am Zehnhoff-Dinnesen; B.C. Carleton; O. Zolk; M. M. van den Heuvel-Eibrink; The PanCareLIFE consortium; the CPNDS Consortium

doi:10.1038/s41698-021-00178-z

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

A. J.M. Meijer^*
, F. A. Diepstraten
, T. Langer
, L. Broer
, I. K. Domingo
, E. Clemens
, A. G. Uitterlinden
, A. C.H. de Vries
, M. van Grotel
, W. P. Vermeij
, R. A. Ozinga
, H. Binder
, J. Byrne
, E. van Dulmen-den Broeder
, M. L. Garrè
, D. Grabow
, P. Kaatsch
, M. Kaiser
, L. Kenborg
, J. F. Winther

C. Rechnitzer, H. Hasle, T. Kepak, K. Kepakova, W. J.E. Tissing, A.L.F. (Anne-Lotte) van der Kooi, L. C.M. Kremer, J. Kruseova, S. M.F. Pluijm, C. E. Kuehni, H. J.H. van der Pal, R. Parfitt, C. Spix, A. Tillmanns, D. Deuster, P. Matulat, G. Calaminus, A. E. Hoetink, S. Elsner, J. Gebauer, H. Lackner, R. Haupt, C. Blattmann, S. J.C.M.M. Neggers, Sharad R. Rassekh, G.E.B. Wright, B. Brooks, A. P. Nagtegaal, B.I. Drögemöller, C.J.D. Ross, A.P. Bhavsar, A.G. am Zehnhoff-Dinnesen, B.C. Carleton, O. Zolk, M. M. van den Heuvel-Eibrink, The PanCareLIFE consortium, the CPNDS Consortium

^*Corresponding author for this work

Princess Máxima Center for Pediatric Oncology
University Hospital for Children and Adolescents Lübeck
University of Alberta
Oncode Institute (Nederland)
University of Freiburg Medical Center
Boyne Research Institute
VU University Medical Center
IRCCS Istituto Giannina Gaslini - Genova
Danish Cancer Society
Aarhus University
Rigshospitalet
Aarhus University Hospital
International Clinical Research Center (FNUSA-ICRC)
Amsterdam UMC
University Children’s Hospital Bern
University Hospital Münster
University Medical Centre Utrecht
University of Lübeck
Medical University of Graz
Klinikum Stuttgart
Johannes Gutenberg University Mainz
Masaryk University School of Medicine
University Medical Centre Groningen
Motol University Hospital
University Hospital Bern
Universitätsklinikum Schleswig-Holstein
BC Children’s Hospital Research Institute, Vancouver
University of British Columbia
Brandenburg Medical School, Rüdersdorf
Masaryk University

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

20 Citations (Scopus)

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Abstract

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Original language	English
Article number	64
Number of pages	8
Journal	npj Precision Oncology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s41698-021-00178-z
Publication status	Published - 14 Jul 2021

Bibliographical note

Funding Information:
We would like to thank all childhood cancer patients and their families for their contribution to this study. PanCareLIFE (PCL) is a collaborative project in the 7th Framework Program of the European Union. PCL partners for this project are University Medical Center Mainz, Germany (P.K., D.G.), Boyne Research Institute, Drogheda, Ireland (J.B., H. Campbell), Pintail Ltd., Dublin, Ireland (Mr. C. Clissmann, Dr. K. O’Brien), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M.K.), University of Lübeck, Germany (T.L.), Amsterdam University Medical Centers, VU Medical Center, Netherlands (Dr. E. van Dulmen-den Broeder, M.H. van den Berg), Erasmus Medical Center Rotterdam, Netherlands (M.M.H.E.), Charité Hospital Berlin, Germany (Professor A. Borgmann-Staudt, Mr. R. Schilling), University of Münster, Germany (A.G.Z.D.), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., Dr. F. Bagnasco), University Hospital Brno, Czech Republic (T.K.), University Hospital Saint Etienne, France (Dr. C. Berger, Dr. L. Casagranda), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), and University Hospital Bonn, Germany (G.C., K.B.). Discovery cohort data in PCL were provided by: Erasmus Medical Center, Netherlands (M.M.H.E.), Princess Máxima Center for Pediatric Oncology, Netherlands (M.M.H.E.), University Medical Center Groningen, Netherlands (W.J.E.T.), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M. K.), University of Munster, Germany (A.G.Z.D., Professor U. Dirksen), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., M.L.G.), The University Hospital Brno, Czech Republic (T.K.), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), Medical University of Graz, Austria (H.L.), Ulm University, Germany (Professor H. Cario, O.Z.), University of Lübeck, Germany (T.L.), Klinikum Stuttgart, Olgahospital, Germany (Professor S. Bielack), and University Hospital Bonn, Germany (G.C.). Replication cohort 1 data were provided by Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Consortium (Vancouver, British Columbia Children’s Hospital, B.C.C., C.J.D.R., S.R.R.; Edmonton, University of Alberta, A.P.B., D.E.; Calgary, Alberta Children’s Hospital, G Guilcher; Winnipeg Health Sciences Centre, J.M., G.’t.J, G.C.; London Health Sciences Centre, M.R.; Toronto, Hospital for Sick Children: S.I., P.N.; Ottawa, Children’s Hospital of Eastern Ontario, R.V., D.J.; Montreal, CHU Sainte‐Justine, J.-F.B., D.L.; Montreal Children’s Hospital, N.J.; Halifax, IWK Health Centre, K.G., K.K.). Replication cohort 2 data were provided by Ulm University, Germany (O.Z.). Age-related hearing loss data were provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, Erasmus Medical Center, Netherlands (A.P.N.). Functional validation experiments were performed at the Department of Medical Microbiology and Immunology, University of Alberta, Canada (A.P.B.), and at the Princess Máxima Center for Pediatric Oncology, Netherlands (W.P.V.). This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no 602030. AM is supported by Stichting Gaby Olthuis Fonds, the Netherlands, under Grant number 2020-003. Functional studies have been supported by funding from the Canadian Institutes of Health Research; PJT-153145 and MY2-155361 to A.B., C.R., and B.C. and recruitment funding from the University of Alberta Li Ka Shing Institute of Virology and Faculty of Medicine & Dentistry to AB, and Oncode to WV and RO. AB holds a (Tier 2) Canada Research Chair (231622) in Functional Genomic Medicine and this research was undertaken, in part, thanks to funding from the Canada Research Chairs Program. This research has also been funded by the generous support of the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute to AB.

Publisher Copyright:
© 2021, The Author(s).

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Meijer, A. J. M., Diepstraten, F. A., Langer, T., Broer, L., Domingo, I. K., Clemens, E., Uitterlinden, A. G., de Vries, A. C. H., van Grotel, M., Vermeij, W. P., Ozinga, R. A., Binder, H., Byrne, J., van Dulmen-den Broeder, E., Garrè, M. L., Grabow, D., Kaatsch, P., Kaiser, M., Kenborg, L., ... the CPNDS Consortium (2021). TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study. npj Precision Oncology, 5(1), Article 64. https://doi.org/10.1038/s41698-021-00178-z

@article{5e402abeced44572860ca2d3c9230410,

title = "TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study",

abstract = "In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.",

author = "Meijer, \{A. J.M.\} and Diepstraten, \{F. A.\} and T. Langer and L. Broer and Domingo, \{I. K.\} and E. Clemens and Uitterlinden, \{A. G.\} and \{de Vries\}, \{A. C.H.\} and \{van Grotel\}, M. and Vermeij, \{W. P.\} and Ozinga, \{R. A.\} and H. Binder and J. Byrne and \{van Dulmen-den Broeder\}, E. and Garr{\`e}, \{M. L.\} and D. Grabow and P. Kaatsch and M. Kaiser and L. Kenborg and Winther, \{J. F.\} and C. Rechnitzer and H. Hasle and T. Kepak and K. Kepakova and Tissing, \{W. J.E.\} and \{van der Kooi\}, \{A.L.F. (Anne-Lotte)\} and Kremer, \{L. C.M.\} and J. Kruseova and Pluijm, \{S. M.F.\} and Kuehni, \{C. E.\} and \{van der Pal\}, \{H. J.H.\} and R. Parfitt and C. Spix and A. Tillmanns and D. Deuster and P. Matulat and G. Calaminus and Hoetink, \{A. E.\} and S. Elsner and J. Gebauer and H. Lackner and R. Haupt and C. Blattmann and Neggers, \{S. J.C.M.M.\} and Rassekh, \{Sharad R.\} and G.E.B. Wright and B. Brooks and Nagtegaal, \{A. P.\} and B.I. Dr{\"o}gem{\"o}ller and C.J.D. Ross and A.P. Bhavsar and \{am Zehnhoff-Dinnesen\}, A.G. and B.C. Carleton and O. Zolk and \{van den Heuvel-Eibrink\}, \{M. M.\} and \{The PanCareLIFE consortium\} and \{the CPNDS Consortium\}",

note = "Funding Information: We would like to thank all childhood cancer patients and their families for their contribution to this study. PanCareLIFE (PCL) is a collaborative project in the 7th Framework Program of the European Union. PCL partners for this project are University Medical Center Mainz, Germany (P.K., D.G.), Boyne Research Institute, Drogheda, Ireland (J.B., H. Campbell), Pintail Ltd., Dublin, Ireland (Mr. C. Clissmann, Dr. K. O{\textquoteright}Brien), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M.K.), University of L{\"u}beck, Germany (T.L.), Amsterdam University Medical Centers, VU Medical Center, Netherlands (Dr. E. van Dulmen-den Broeder, M.H. van den Berg), Erasmus Medical Center Rotterdam, Netherlands (M.M.H.E.), Charit{\'e} Hospital Berlin, Germany (Professor A. Borgmann-Staudt, Mr. R. Schilling), University of M{\"u}nster, Germany (A.G.Z.D.), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., Dr. F. Bagnasco), University Hospital Brno, Czech Republic (T.K.), University Hospital Saint Etienne, France (Dr. C. Berger, Dr. L. Casagranda), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), and University Hospital Bonn, Germany (G.C., K.B.). Discovery cohort data in PCL were provided by: Erasmus Medical Center, Netherlands (M.M.H.E.), Princess M{\'a}xima Center for Pediatric Oncology, Netherlands (M.M.H.E.), University Medical Center Groningen, Netherlands (W.J.E.T.), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M. K.), University of Munster, Germany (A.G.Z.D., Professor U. Dirksen), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., M.L.G.), The University Hospital Brno, Czech Republic (T.K.), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), Medical University of Graz, Austria (H.L.), Ulm University, Germany (Professor H. Cario, O.Z.), University of L{\"u}beck, Germany (T.L.), Klinikum Stuttgart, Olgahospital, Germany (Professor S. Bielack), and University Hospital Bonn, Germany (G.C.). Replication cohort 1 data were provided by Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Consortium (Vancouver, British Columbia Children{\textquoteright}s Hospital, B.C.C., C.J.D.R., S.R.R.; Edmonton, University of Alberta, A.P.B., D.E.; Calgary, Alberta Children{\textquoteright}s Hospital, G Guilcher; Winnipeg Health Sciences Centre, J.M., G.{\textquoteright}t.J, G.C.; London Health Sciences Centre, M.R.; Toronto, Hospital for Sick Children: S.I., P.N.; Ottawa, Children{\textquoteright}s Hospital of Eastern Ontario, R.V., D.J.; Montreal, CHU Sainte‐Justine, J.-F.B., D.L.; Montreal Children{\textquoteright}s Hospital, N.J.; Halifax, IWK Health Centre, K.G., K.K.). Replication cohort 2 data were provided by Ulm University, Germany (O.Z.). Age-related hearing loss data were provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, Erasmus Medical Center, Netherlands (A.P.N.). Functional validation experiments were performed at the Department of Medical Microbiology and Immunology, University of Alberta, Canada (A.P.B.), and at the Princess M{\'a}xima Center for Pediatric Oncology, Netherlands (W.P.V.). This work was supported by the PanCareLIFE project that has received funding from the European Union{\textquoteright}s Seventh Framework Program for research, technological development and demonstration under grant agreement no 602030. AM is supported by Stichting Gaby Olthuis Fonds, the Netherlands, under Grant number 2020-003. Functional studies have been supported by funding from the Canadian Institutes of Health Research; PJT-153145 and MY2-155361 to A.B., C.R., and B.C. and recruitment funding from the University of Alberta Li Ka Shing Institute of Virology and Faculty of Medicine \& Dentistry to AB, and Oncode to WV and RO. AB holds a (Tier 2) Canada Research Chair (231622) in Functional Genomic Medicine and this research was undertaken, in part, thanks to funding from the Canada Research Chairs Program. This research has also been funded by the generous support of the Stollery Children{\textquoteright}s Hospital Foundation through the Women and Children{\textquoteright}s Health Research Institute to AB. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

day = "14",

doi = "10.1038/s41698-021-00178-z",

language = "English",

volume = "5",

journal = "npj Precision Oncology",

issn = "2397-768X",

publisher = "Nature Research",

number = "1",

}

Meijer, AJM, Diepstraten, FA, Langer, T, Broer, L, Domingo, IK, Clemens, E, Uitterlinden, AG, de Vries, ACH, van Grotel, M, Vermeij, WP, Ozinga, RA, Binder, H, Byrne, J, van Dulmen-den Broeder, E, Garrè, ML, Grabow, D, Kaatsch, P, Kaiser, M, Kenborg, L, Winther, JF, Rechnitzer, C, Hasle, H, Kepak, T, Kepakova, K, Tissing, WJE, van der Kooi, ALF, Kremer, LCM, Kruseova, J, Pluijm, SMF, Kuehni, CE, van der Pal, HJH, Parfitt, R, Spix, C, Tillmanns, A, Deuster, D, Matulat, P, Calaminus, G, Hoetink, AE, Elsner, S, Gebauer, J, Lackner, H, Haupt, R, Blattmann, C, Neggers, SJCMM, Rassekh, SR, Wright, GEB, Brooks, B, Nagtegaal, AP, Drögemöller, BI, Ross, CJD, Bhavsar, AP, am Zehnhoff-Dinnesen, AG, Carleton, BC, Zolk, O, van den Heuvel-Eibrink, MM, The PanCareLIFE consortium & the CPNDS Consortium 2021, 'TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study', npj Precision Oncology, vol. 5, no. 1, 64. https://doi.org/10.1038/s41698-021-00178-z

TY - JOUR

T1 - TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

AU - Meijer, A. J.M.

AU - Diepstraten, F. A.

AU - Langer, T.

AU - Broer, L.

AU - Domingo, I. K.

AU - Clemens, E.

AU - Uitterlinden, A. G.

AU - de Vries, A. C.H.

AU - van Grotel, M.

AU - Vermeij, W. P.

AU - Ozinga, R. A.

AU - Binder, H.

AU - Byrne, J.

AU - van Dulmen-den Broeder, E.

AU - Garrè, M. L.

AU - Grabow, D.

AU - Kaatsch, P.

AU - Kaiser, M.

AU - Kenborg, L.

AU - Winther, J. F.

AU - Rechnitzer, C.

AU - Hasle, H.

AU - Kepak, T.

AU - Kepakova, K.

AU - Tissing, W. J.E.

AU - van der Kooi, A.L.F. (Anne-Lotte)

AU - Kremer, L. C.M.

AU - Kruseova, J.

AU - Pluijm, S. M.F.

AU - Kuehni, C. E.

AU - van der Pal, H. J.H.

AU - Parfitt, R.

AU - Spix, C.

AU - Tillmanns, A.

AU - Deuster, D.

AU - Matulat, P.

AU - Calaminus, G.

AU - Hoetink, A. E.

AU - Elsner, S.

AU - Gebauer, J.

AU - Lackner, H.

AU - Haupt, R.

AU - Blattmann, C.

AU - Neggers, S. J.C.M.M.

AU - Rassekh, Sharad R.

AU - Wright, G.E.B.

AU - Brooks, B.

AU - Nagtegaal, A. P.

AU - Drögemöller, B.I.

AU - Ross, C.J.D.

AU - Bhavsar, A.P.

AU - am Zehnhoff-Dinnesen, A.G.

AU - Carleton, B.C.

AU - Zolk, O.

AU - van den Heuvel-Eibrink, M. M.

AU - The PanCareLIFE consortium

AU - the CPNDS Consortium

N1 - Funding Information: We would like to thank all childhood cancer patients and their families for their contribution to this study. PanCareLIFE (PCL) is a collaborative project in the 7th Framework Program of the European Union. PCL partners for this project are University Medical Center Mainz, Germany (P.K., D.G.), Boyne Research Institute, Drogheda, Ireland (J.B., H. Campbell), Pintail Ltd., Dublin, Ireland (Mr. C. Clissmann, Dr. K. O’Brien), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M.K.), University of Lübeck, Germany (T.L.), Amsterdam University Medical Centers, VU Medical Center, Netherlands (Dr. E. van Dulmen-den Broeder, M.H. van den Berg), Erasmus Medical Center Rotterdam, Netherlands (M.M.H.E.), Charité Hospital Berlin, Germany (Professor A. Borgmann-Staudt, Mr. R. Schilling), University of Münster, Germany (A.G.Z.D.), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., Dr. F. Bagnasco), University Hospital Brno, Czech Republic (T.K.), University Hospital Saint Etienne, France (Dr. C. Berger, Dr. L. Casagranda), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), and University Hospital Bonn, Germany (G.C., K.B.). Discovery cohort data in PCL were provided by: Erasmus Medical Center, Netherlands (M.M.H.E.), Princess Máxima Center for Pediatric Oncology, Netherlands (M.M.H.E.), University Medical Center Groningen, Netherlands (W.J.E.T.), Amsterdam University Medical Centers, University of Amsterdam, Netherlands (L.C.M. K.), University of Munster, Germany (A.G.Z.D., Professor U. Dirksen), University of Bern, Switzerland (C.E.K.), IRCCS Istituto Giannina Gaslini, Genova, Italy (R.H., M.L.G.), The University Hospital Brno, Czech Republic (T.K.), Danish Cancer Society, Copenhagen, Denmark (J.F.W.), Motol University Hospital, Prague, Czech Republic (J.K.), Medical University of Graz, Austria (H.L.), Ulm University, Germany (Professor H. Cario, O.Z.), University of Lübeck, Germany (T.L.), Klinikum Stuttgart, Olgahospital, Germany (Professor S. Bielack), and University Hospital Bonn, Germany (G.C.). Replication cohort 1 data were provided by Canadian Pharmacogenomics Network for Drug Safety (CPNDS) Consortium (Vancouver, British Columbia Children’s Hospital, B.C.C., C.J.D.R., S.R.R.; Edmonton, University of Alberta, A.P.B., D.E.; Calgary, Alberta Children’s Hospital, G Guilcher; Winnipeg Health Sciences Centre, J.M., G.’t.J, G.C.; London Health Sciences Centre, M.R.; Toronto, Hospital for Sick Children: S.I., P.N.; Ottawa, Children’s Hospital of Eastern Ontario, R.V., D.J.; Montreal, CHU Sainte‐Justine, J.-F.B., D.L.; Montreal Children’s Hospital, N.J.; Halifax, IWK Health Centre, K.G., K.K.). Replication cohort 2 data were provided by Ulm University, Germany (O.Z.). Age-related hearing loss data were provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, Erasmus Medical Center, Netherlands (A.P.N.). Functional validation experiments were performed at the Department of Medical Microbiology and Immunology, University of Alberta, Canada (A.P.B.), and at the Princess Máxima Center for Pediatric Oncology, Netherlands (W.P.V.). This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no 602030. AM is supported by Stichting Gaby Olthuis Fonds, the Netherlands, under Grant number 2020-003. Functional studies have been supported by funding from the Canadian Institutes of Health Research; PJT-153145 and MY2-155361 to A.B., C.R., and B.C. and recruitment funding from the University of Alberta Li Ka Shing Institute of Virology and Faculty of Medicine & Dentistry to AB, and Oncode to WV and RO. AB holds a (Tier 2) Canada Research Chair (231622) in Functional Genomic Medicine and this research was undertaken, in part, thanks to funding from the Canada Research Chairs Program. This research has also been funded by the generous support of the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute to AB. Publisher Copyright: © 2021, The Author(s).

PY - 2021/7/14

Y1 - 2021/7/14

N2 - In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

AB - In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

UR - https://www.scopus.com/pages/publications/85117051914

U2 - 10.1038/s41698-021-00178-z

DO - 10.1038/s41698-021-00178-z

M3 - Article

C2 - 34262104

AN - SCOPUS:85117051914

SN - 2397-768X

VL - 5

JO - npj Precision Oncology

JF - npj Precision Oncology

IS - 1

M1 - 64

ER -

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

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