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37. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP)

Deutsche Gesellschaft für Phoniatrie und Pädaudiologie e. V.

17.09. - 18.09.2021, digital

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

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  • corresponding author presenting/speaker A. Meijer - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • F. A. Diepstraten - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • T. Langer - Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany
  • L. Broer - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • I. K. Domingo - Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada
  • E. Clemens - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • A. G. Uitterlinden - Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
  • A. C. H. de Vries - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • M. van Grotel - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • W. P. Vermeij - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • R. A. Ozinga - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • H. Binder - German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • J. Byrne - Boyne Research Institute, Drogheda, Ireland
  • E. van Dulmen-den Broeder - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • M. L. Garrè - Department of Neurooncology, IRCCS Istituto Giannina Gaslini, Genova, Italy
  • D. Grabow - German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • P. Kaatsch - German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • M. Kaiser - German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • L. Kenborg - Childhood Cancer Research Group, Danish Cancer Society Research Center, Kopenhagen, Denmark
  • J. Falck-Winther - Childhood Cancer Research Group, Danish Cancer Society Research Center, Kopenhagen, Denmark
  • C. Rechnitzer - Copenhagen University Hospital Rigshospitalet, Department of Pediatrics and Adolescent Medicine, Kopenhagen, Denmark
  • H. Hasle - Aarhus University Hospital, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
  • T. Kepak - University Hospital Brno, Brno, Czech Republic; International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic
  • K. Kepakova - University Hospital Brno, Brno, Czech Republic; International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic
  • W. J. E. Tissing - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • A. L. F. van der Kooi - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • L. C. Kremer - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • J. Kruseova - Department of Children Hemato-Oncology, Motol University Hospital Prague, Prag, Czech Republic
  • S. M. F. Pluijm - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • C. F. Kuehni - Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  • H. van der Pal - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • R. Parfitt - Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany
  • C. Spix - German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • A. Hesping - Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany
  • D. Deuster - Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany
  • P. Matulat - Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany
  • G. Calaminus - Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany
  • A. E. Hoetink - Department of Audiology, University Hospital Utrecht, Utrecht, Netherlands
  • S. Elsner - Institute of Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany
  • J. Gebauer - Department of Internal Medicine, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
  • R. Haupt - Epidemiology and Biostatistics Unit and DOPO Clinic, IRCCS Istituto Giannina Gaslini, Genua, Italy
  • H. Lackner - Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria
  • C. Blattmann - Klinikum Stuttgart, Olgahospital, Pediatrics, Oncology, Hematology, Immunology, Stuttgart, Germany
  • S. J. C. M. M. Neggers - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
  • S. R. Rassekh - BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • G. E. B. Wright - BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • B. Brooks - Audiology and Speech Pathology Department, BC Children’s Hospital, Vancouver, British Columbia, Canada
  • A. P. Nagtegaal - Departement of Otorhinolaryngology, Erasmus Medical Center, Rotterdam, Netherlands
  • B. I. Drögemöller - BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • C. J. D. Ross - BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • A. P. Bhavsar - Department of Pediatric Oncology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, Netherlands
  • A. am Zehnhoff-Dinnesen - Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany
  • B. C. Carleton - BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • O. Zolk - Institute of Clinical Pharmacology, Brandenburg Medical School, Rüdersdorf, Germany
  • author M. van den Heuvel-Eibrink - Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

37. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP). sine loco [digital], 17.-18.09.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocP15

doi: 10.3205/21dgpp30, urn:nbn:de:0183-21dgpp302

Veröffentlicht: 28. Oktober 2021

© 2021 Meijer et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Zusammenfassung

Background: Ototoxicity (hearing loss, tinnitus and/or vertigo) is a serious adverse event of cisplatin treatment in children with cancer. The heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. This study investigated the association between carriership of novel single nucleotide polymorphisms (SNPs) and cisplatin-induced hearing loss (CIHL) in childhood cancer patients.

Material and methods: The discovery cohort included cisplatin treated, non-cranial irradiated pediatric cancer patients within the European PanCareLIFE (PCL) study (N=390). CIHL at end of cancer treatment was defined as Muenster grade ≥2b, assessed by pure tone audiometry. DNA was genotyped using the Infinium© Global Screening Array. Logistic regression models were applied including age at diagnosis, sex, cisplatin total cumulative dose and principal components 1–4, assuming an additive effect of the minor allele. Replication of the findings was performed in two independent, similarly treated cohorts (N=192 and N=188). Functional validation experiments in cultured human HeLa cell lines were performed to determine the effect of knockdown of the SNPs nearest identified gene on cisplatin-induced toxicity.

Results: In the PCL discovery cohort, 8 SNPs reached a suggestive significance of P<1.0x10-5. One variant (rs893507) within the TCERG1L gene showed evidence of replication (P=0.01) in the Canadian first replication cohort. Analysis in the PCL second replication cohort confirmed this finding (P=1.0x10-4). The combined analysis showed that carriership of the C-allele of this newly discovered variant increases the odds of CIHL with 3.11-fold (P=5.3x10-10, 95% CI 2.2–4.5). Modulating TCERG1L expression significantly altered cell viability in response to cisplatin treatment, where TCERG1L overexpression and silencing protected and sensitized cells to cisplatin toxicity, respectively.

Discussion: Children with cancer who carry a variant in the TCERG1L gene appear to have higher odds of hearing loss related to cisplatin.

Conclusion: The results of this study contribute to novel insights into the genetic and pathophysiological basis of CIHL.

Gliederung

Text

Background

Cisplatin is a highly effective chemotherapeutic agent for an important subset of childhood cancers. However, the occurrence of irreversible hearing loss in approximately 50% of treated children is a serious clinical challenge [1]. Understanding the biology of cisplatin-induced hearing loss (CIHL) is highly relevant as children are at a critical stage of their speech and language development, with the added risk of experiencing social, emotional, or vocational difficulties related to hearing loss [2]. The heterogeneity in CIHL occurrence after similar treatment suggests a role for genetic susceptibility. By using a Genome-Wide Association Study, we investigated the association between carriership of novel single nucleotide polymorphisms (SNPs) and CIHL in childhood cancer patients.

Materials and Methods

The discovery cohort consists of childhood cancer patients from the European PanCareLIFE (PCL) consortium [3]. Included patients were diagnosed with cancer before the age of 19 years, were initially treated with cisplatin, did not receive cranial or inner ear radiation and did not have baseline hearing loss. Patient, audiological and treatment-related data were collected retrospectively from medical records. CIHL at end of cancer treatment was defined as Muenster grade ≥2b, assessed by pure tone audiometry. DNA was isolated from blood and saliva samples, and was genotyped using the Infinium© Global Screening Array. For the GWAS analyses, logistic regression models were applied including age at diagnosis, sex, cisplatin total cumulative dose and (TCD) principal components 1–4, assuming an additive effect of the minor allele. Variants with suggestive levels of association (P<1x10-5) were pursued for replication, which was performed in two independent, similarly treated cohorts from Canada and Europe. Functional validation experiments in cultured human HeLa cell lines and mouse tissues were performed to determine the effect of knockdown or overexpression of the SNPs nearest identified gene on cisplatin-induced toxicity and cisplatin-induced inflammatory cytokine production.

Results

The PCL discovery cohort included 390 patients, of whom 168 (43%) suffered from CIHL. Eight SNPs reached a suggestive significance of P<1.0x10-5. One variant (rs893507) within the TCERG1L gene showed evidence of replication (P=0.01) in the Canadian first replication cohort (N=192). Analysis in the European second replication cohort (N=188) confirmed this finding (P=1.0x10-4). The combined analysis showed that carriership of the C-allele of this variant increases the odds of CIHL with 3.11-fold (P=5.3x10-10, 95% CI 2.2–4.5) (Figure 1 [Fig. 1]). In HeLa cells, modulating TCERG1L expression significantly altered cell viability in response to cisplatin treatment, where TCERG1L overexpression and silencing protected and sensitized cells to cisplatin toxicity, respectively. TCERG1L overexpression reduced pro-inflammatory IL-8 cytokine secretion in response to cisplatin treatment; whereas TCERG1L-silencing had the opposite effect. This inverse correlation was also found between TCERG1L mRNA expression and pro-inflammatory cytokine IL-6 expression in response to cisplatin treatment by RNA-seq in mouse tissues (Figure 2 [Fig. 2]).

Discussion

The TCERG1L gene has not been associated previously with chemotherapy-induced hearing loss. Previous studies revealed an association with inflammatory bowel disease and colon cancer suggesting that TCERG1L influences immunological pathways [4], [5]. In addition, TCERG1L might be expressed in human cochlear inner and outer hair cells [6] as well as murine inner hair cells [7]. That this variant in TCERG1L was not identified previously might be attributable to differences in cohort characteristics, platinum agents, and radiotherapy that may overrule the effect of genetics. A strength of the study is the sample size (N=770), which is relatively large considering that childhood cancer is very rare. A limitation is that a robust assessment of ototoxic co-medications and their potential influence on the strength of the TCERG1L genetic association could not be performed, because retrospective patient data did not capture complete details of these co-medications.

Conclusion

Children with cancer who carry a variant in the TCERG1L gene appear to have higher odds of hearing loss related to cisplatin. Our study shows statistical and functional evidence for the involvement of TCERG1L in cisplatin-induced inflammatory response and toxicity. Even though cochlear inflammation induced by cisplatin can lead to inner ear damage and hearing loss, future studies are needed to further validate the functional impact of the variant related to hearing loss, preferably by use of human cochlear sections.

Gliederung

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