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 435233 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.
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 435233 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.
Authors: Penelope R Brock; Kristin R Knight; David R Freyer; Kathleen C M Campbell; Peter S Steyger; Brian W Blakley; Shahrad R Rassekh; Kay W Chang; Brian J Fligor; Kaukab Rajput; Michael Sullivan; Edward A Neuwelt Journal: J Clin Oncol Date: 2012-04-30 Impact factor: 44.544
Authors: Hyang-Min Byun; Kimberly D Siegmund; Fei Pan; Daniel J Weisenberger; Gary Kanel; Peter W Laird; Allen S Yang Journal: Hum Mol Genet Date: 2009-09-23 Impact factor: 6.150
Authors: Tara M Brinkman; Johnnie K Bass; Zhenghong Li; Kirsten K Ness; Amar Gajjar; Alberto S Pappo; Gregory T Armstrong; Thomas E Merchant; Deo Kumar Srivastava; Leslie L Robison; Melissa M Hudson; James G Gurney Journal: Cancer Date: 2015-08-19 Impact factor: 6.860
Authors: Colin J D Ross; Hagit Katzov-Eckert; Marie-Pierre Dubé; Beth Brooks; S Rod Rassekh; Amina Barhdadi; Yassamin Feroz-Zada; Henk Visscher; Andrew M K Brown; Michael J Rieder; Paul C Rogers; Michael S Phillips; Bruce C Carleton; Michael R Hayden Journal: Nat Genet Date: 2009-11-08 Impact factor: 38.330
Authors: Howard M Katzenstein; Kay W Chang; Mark Krailo; Zhengjia Chen; Milton J Finegold; Jon Rowland; Marleta Reynolds; Alberto Pappo; Wendy B London; Marcio Malogolowkin Journal: Cancer Date: 2009-12-15 Impact factor: 6.860
Authors: Melanie M Hagleitner; Marieke J H Coenen; Ana Patino-Garcia; Eveline S J M de Bont; Anna Gonzalez-Neira; Hanneke I Vos; Frank N van Leeuwen; Hans Gelderblom; Peter M Hoogerbrugge; Henk-Jan Guchelaar; Maroeska W M Te Loo Journal: PLoS One Date: 2014-12-31 Impact factor: 3.240
Authors: Austin L Brown; Philip J Lupo; Mehmet Fatih Okcu; Ching C Lau; Surya Rednam; Michael E Scheurer Journal: Cancer Med Date: 2015-09-24 Impact factor: 4.452
Authors: Philip J Lupo; Lauren M Petrick; Thanh T Hoang; Amanda E Janitz; Erin L Marcotte; Jeremy M Schraw; Manish Arora; Michael E Scheurer Journal: Bioessays Date: 2021-06-09 Impact factor: 4.653
Authors: Evangelia Tserga; Tara Nandwani; Niklas K Edvall; Jan Bulla; Poulam Patel; Barbara Canlon; Christopher R Cederroth; David M Baguley Journal: Sci Rep Date: 2019-03-05 Impact factor: 4.379