DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors

Austin L. Brown, Kayla L. Foster, Philip J. Lupo, Erin C. Peckham-Gregory, Jeffrey C. Murray, M. Fatih Okcu, Ching C. Lau, Surya P. Rednam, Murali Chintagumpala, Michael E. Scheurer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background. Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Methods. Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. Results. The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435 233 CpG sites, 6 sites were associated with ototoxicity grade (P 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders. Conclusions. We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.

Original languageEnglish (US)
Pages (from-to)1372-1379
Number of pages8
JournalNeuro-oncology
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2017

Keywords

  • Adverse treatment effects
  • DNA methylation
  • Ototoxicity
  • Pediatric embryonal cancer
  • Survivorship

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Fingerprint Dive into the research topics of 'DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors'. Together they form a unique fingerprint.

Cite this