Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss

Nature Genetics volume 47, pages 263–266 (2015)Cite this article

Subjects

A Corrigendum to this article was published on 27 March 2015

This article has been updated

Abstract

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10−8, hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genome-wide association results of cisplatin-induced ototoxicity.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Change history

  • 13 March 2015

    In the version of this article initially published, the authors neglected to acknowledge that the work was also supported by US National Institutes of Health grant R01 CA154619. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Cheung, N.V. & Heller, G. Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J. Clin. Oncol. 9, 1050–1058 (1991).

    Article  CAS  Google Scholar 

  2. Perilongo, G. et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N. Engl. J. Med. 361, 1662–1670 (2009).

    Article  CAS  Google Scholar 

  3. Williams, S.D. et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N. Engl. J. Med. 316, 1435–1440 (1987).

    Article  CAS  Google Scholar 

  4. Brock, P.R. et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J. Clin. Oncol. 30, 2408–2417 (2012).

    Article  CAS  Google Scholar 

  5. Langer, T., am Zehnhoff-Dinnesen, A., Radtke, S., Meitert, J. & Zolk, O. Understanding platinum-induced ototoxicity. Trends Pharmacol. Sci. 34, 458–469 (2013).

    Article  CAS  Google Scholar 

  6. Qaddoumi, I. et al. Carboplatin-associated ototoxicity in children with retinoblastoma. J. Clin. Oncol. 30, 1034–1041 (2012).

    Article  CAS  Google Scholar 

  7. Dean, J.B. et al. Hearing loss in pediatric oncology patients receiving carboplatin-containing regimens. J. Pediatr. Hematol. Oncol. 30, 130–134 (2008).

    Article  CAS  Google Scholar 

  8. Kushner, B.H., Budnick, A., Kramer, K., Modak, S. & Cheung, N.K. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107, 417–422 (2006).

    Article  CAS  Google Scholar 

  9. Chen, W.C. et al. Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma. Cancer 106, 820–829 (2006).

    Article  Google Scholar 

  10. Li, Y., Womer, R.B. & Silber, J.H. Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur. J. Cancer 40, 2445–2451 (2004).

    Article  CAS  Google Scholar 

  11. Oldenburg, J., Kraggerud, S.M., Cvancarova, M., Lothe, R.A. & Fossa, S.D. Cisplatin-induced long-term hearing impairment is associated with specific glutathione S-transferase genotypes in testicular cancer survivors. J. Clin. Oncol. 25, 708–714 (2007).

    Article  CAS  Google Scholar 

  12. Fouladi, M. et al. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J. Clin. Oncol. 26, 3749–3755 (2008).

    Article  CAS  Google Scholar 

  13. Travis, L.B. et al. Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics. J. Natl. Cancer Inst. 106, dju044 (2014).

    Article  Google Scholar 

  14. Mukherjea, D. & Rybak, L.P. Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics 12, 1039–1050 (2011).

    Article  CAS  Google Scholar 

  15. Gurney, J.G. et al. Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma. Neuro-oncol. 16, 848–855 (2014).

    Article  CAS  Google Scholar 

  16. Ross, C.J. et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat. Genet. 41, 1345–1349 (2009).

    Article  CAS  Google Scholar 

  17. Pussegoda, K. et al. Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin. Pharmacol. Ther. 94, 243–251 (2013).

    Article  CAS  Google Scholar 

  18. Yang, J.J. et al. The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer. Clin. Pharmacol. Ther. 94, 252–259 (2013).

    Article  CAS  Google Scholar 

  19. Lanvers-Kaminsky, C. et al. Evaluation of pharmacogenetic markers to predict the risk of cisplatin-induced ototoxicity. Clin. Pharmacol. Ther. 96, 156–157 (2014).

    Article  CAS  Google Scholar 

  20. Ratain, M.J., Cox, N.J. & Henderson, T.O. Challenges in interpreting the evidence for genetic predictors of ototoxicity. Clin. Pharmacol. Ther. 94, 631–635 (2013).

    Article  CAS  Google Scholar 

  21. Boddy, A.V. Genetics of cisplatin ototoxicity: confirming the unexplained? Clin. Pharmacol. Ther. 94, 198–200 (2013).

    Article  CAS  Google Scholar 

  22. Landier, W. et al. Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales—a report from the Children's Oncology Group. J. Clin. Oncol. 32, 527–534 (2014).

    Article  Google Scholar 

  23. Bass, J.K. et al. Concordance between the Chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma. Pediatr. Blood Cancer 61, 601–605 (2014).

    Article  Google Scholar 

  24. Won, H.H. et al. Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer 118, 2828–2836 (2012).

    Article  CAS  Google Scholar 

  25. Oguri, T. et al. Genetic polymorphisms associated with oxaliplatin-induced peripheral neurotoxicity in Japanese patients with colorectal cancer. Int. J. Clin. Pharmacol. Ther. 51, 475–481 (2013).

    Article  CAS  Google Scholar 

  26. Degl'Innocenti, D. et al. Acylphosphatase expression during macrophage differentiation and activation of U-937 cell line. Biochimie 81, 1031–1035 (1999).

    Article  CAS  Google Scholar 

  27. Liu, H. et al. Characterization of transcriptomes of cochlear inner and outer hair cells. J. Neurosci. 34, 11085–11095 (2014).

    Article  Google Scholar 

  28. Fuchs, P.A. A 'calcium capacitor' shapes cholinergic inhibition of cochlear hair cells. J. Physiol. (Lond.) 592, 3393–3401 (2014).

    Article  CAS  Google Scholar 

  29. Thomas, A.J. et al. Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line. J. Neurosci. 33, 4405–4414 (2013).

    Article  CAS  Google Scholar 

  30. Gajjar, A. et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St. Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 7, 813–820 (2006).

    Article  Google Scholar 

  31. Chang, K.W. & Chinosornvatana, N. Practical grading system for evaluating cisplatin ototoxicity in children. J. Clin. Oncol. 28, 1788–1795 (2010).

    Article  CAS  Google Scholar 

  32. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  33. Potter, D.M. A permutation test for inference in logistic regression with small- and moderate-sized data sets. Stat. Med. 24, 693–708 (2005).

    Article  Google Scholar 

  34. Fine, J.P. & Gray, R.J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509 (1999).

    Article  Google Scholar 

  35. Huang, R.S. et al. Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am. J. Hum. Genet. 81, 427–437 (2007).

    Article  CAS  Google Scholar 

  36. Choy, E. et al. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 4, e1000287 (2008).

    Article  Google Scholar 

Download references

Acknowledgements

We thank S. Throm for coordinating patient samples, S. Hughes for curating the ototoxicity data, all patients and their parents who participated in the St. Jude protocols included in this study, G. Koh (National University of Singapore) for her assistance in genome-wide genotyping, and L. Robison and K. Ness (St. Jude Children's Research Hospital) for insightful discussions. This work was supported by the US National Institutes of Health (P30 CA21765-34, U01 GM92666 and R01 CA154619) and the American Lebanese Syrian Associated Charities (ALSAC).

Author information

Author notes

  1. Heng Xu and Giles W Robinson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Heng Xu, Joshua Yew-Suang Lim, Hui Zhang, Clinton F Stewart & Jun J Yang

  2. Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Heng Xu

  3. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Giles W Robinson, Alberto Broniscer & Amar Gajjar

  4. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Jie Huang & Arzu Onar-Thomas

  5. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Joshua Yew-Suang Lim

  6. Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Johnnie K Bass

  7. Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA

    Murali Chintagumpala

  8. Department of Haematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

    Ute Bartels

  9. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA

    Sri Gururangan

  10. Department of Oncology, The Royal Children's Hospital, Parkville, Victoria, Australia

    Tim Hassall

  11. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Michael Fisher

  12. School of Women's and Children's Health, University of New South Wales, Kensington, New South Wales, Australia

    Richard Cohn

  13. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Tetsuji Yamashita, Tal Teitz & Jian Zuo

Authors
  1. Heng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giles W Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joshua Yew-Suang Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johnnie K Bass
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alberto Broniscer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Murali Chintagumpala
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ute Bartels
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sri Gururangan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tim Hassall
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Richard Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tetsuji Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tal Teitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jian Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Arzu Onar-Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Amar Gajjar
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Clinton F Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jun J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.J.Y. and C.F.S. supervised the research. A.G., G.W.R., A.B., M.C., U.B., S.G., T.H., M.F. and R.C. provided the study materials or patients. G.W.R., J.K.B., A.G., C.F.S., J.Y.-S.L., H.Z., T.T. and T.Y. collected and assembled the data. H.X., A.O.-T., J.H., J.Y.-S.L. and J.Z. analyzed and interpreted the data. All authors wrote and approved the manuscript.

Corresponding authors

Correspondence to Clinton F Stewart or Jun J Yang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 SJMB96 and SJMB03 treatment protocols.

Children with newly diagnosed brain tumors (primarily medulloblastoma) were enrolled on these two frontline protocols between 1996–2003 and 2003–2012, respectively. Patients were first treated with different dosages of irradiation depending upon risk groups, followed by four cycles of cisplatin-containing chemotherapy.

Supplementary Figure 2 Flowchart of patients' inclusion/exclusion for the genetic analyses in the discovery GWAS series (SJMB96 and SJMB03).

Patients were included in the GWAS series on the basis of the availability of germline DNA and audiology assessments, and no significant difference was observed in demographic or clinical features between patients included and excluded.

Supplementary Figure 3 Ototoxicity onset in SJMB96 and SJMB03.

The majority of ototoxic events occurred within 6 months of the initiation of cisplatin therapy; 60% of the children had detectable hearing loss (Chang grade > 0; blue), and 35% required a hearing aid (Chang grade ≥ 2a; red). Cisplatin-related hearing loss assessment was based on audiology data between 9 and 24 months from the initiation of therapy. The audiology examination closest to 24 months and the worse grade for the two ears were used to determine ototoxicity status. The red arrow indicates the initiation of cisplatin therapy.

Supplementary Figure 4 SNP quality control and filtering in the discovery GWAS.

SNPs were filtered on the basis of allele frequency and call rate (Online Methods).

Supplementary Figure 5 Association results of SNPs around the top GWAS signal at the ACYP2 locus in the discovery GWAS.

Regional plots showed association at SNPs within a 300-kb window (chr. 2: 54.25–54.55 Mb) at the ACYP2 locus. The plots were constructed using LocusZoom (Bioinformatics 26, 2336–2337, 2010): P values (–log10 P values; y axis) are plotted against the respective chromosomal position of each SNP (x axis), and colors indicate LD (r2) with the top signal in 1000 Genomes Project European populations.

Supplementary Figure 6 Associations of ACYP2 SNP (rs1872328) genotype with cisplatin-induced ototoxicity, stratifying on ancestry, craniospinal irradiation and treatment protocols.

Risk allele frequency at rs1872328 is plotted for patients with different degrees of ototoxicity including patients from all ancestry groups (a) and genetically defined European Americans only (b). (c,d) The risk allele (A allele) frequency of rs1872328 increased in parallel with the severity of hearing loss (Chang grades), regardless of craniospinal irradiation dose (c) or treatment protocols (d).

Supplementary Figure 7 Flowchart of patients' inclusion/exclusion for the genetic analyses in the replication series (SJYC07).

Patients were included in the replication series on the basis of the availability of germline DNA and audiology assessments.

Supplementary Figure 8 Exonic variants in ACYP2 identified by targeted resequencing.

Variants in exonic regions of ACYP2 were examined by Sanger sequencing in 257 children included in the discovery GWAS and replication cohort. (a) Boxes indicate four exons of ACYP2 including the coding region (red) and UTRs (blue). Triangles, circles and squares denote UTR, silent and missense variants, respectively. Each shape represents a patient carrying the variant, with open and filled shapes indicating individuals negative or positive for ototoxicity, respectively. (b) Details for all four exonic variants and the nine patients who carried these variants. *“N” indicates novel variants not present in dbSNP.

Supplementary Figure 9 ACYP2 expression and cisplatin treatment response.

ACYP2 expression levels (retrieved from GSE11582 in the NCBI GEO database) are positively related to cisplatin IC50 (Am. J. Hum. Genet. 81, 427–437, 2007) in HapMap CEU lymphoblastoid cell lines.

Supplementary Figure 10 Acyp2 expression in mouse hair cells.

Expression of Acyp2 was determined by RNA-seq of utricle and cochlea hair cells at four different time points (embryonic day 16 and postnatal days 0, 4, and 7; SHIELD database, https://shield.hms.harvard.edu/; J. Neurosci. 34, 11085–11095, 2014).

Supplementary Figure 11 Genetic ancestry distribution in the discovery GWAS cohort.

Genetic ancestry was assessed by principal-component analysis of genome-wide SNP genotype. The top two principal components are shown, and colors discriminate different self-reported ancestry groups.

Supplementary Figure 12 Quantile-quantile (Q-Q) plot of the discovery GWAS results.

The negative logarithm of the observed (y axis) and the expected (x axis) P value is plotted for each SNP (dot), and the black line indicates the null hypothesis of no true association. Deviation from the expected P-value distribution is evident only in the tail area (λ = 1.04), suggesting that population stratification was adequately controlled.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12, Supplementary Note and Supplementary Tables 1–5. (PDF 3557 kb)

Supplementary Data

Data used to generate the Manhattan plot shown in Figure 1a. (ZIP 14728 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, H., Robinson, G., Huang, J. et al. Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss. Nat Genet 47, 263–266 (2015). https://doi.org/10.1038/ng.3217

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3217

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research