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

Abstract

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.

The genetic vulnerability to cisplatin ototoxicity: a systematic review

“…From the 30 included papers, 44% were retrospective with a sample size ranging from 39 to 317 (Table 1). Some of them (33%) were performed on patients younger than 25 years of age 30,37–47 and 80% on both genders. The ethnicity was rather broad with Northern America and Norwegians representing together the majority of the articles (14%) 31,41,48–50 .…”

“…Fifty-three percent of the studies were performed on osteosarcoma 32,37–40,42–44,46,47,51,56–60 , medulloblastoma in 33% 30,32,38–41,44–46,56 , while testicular cancer was studied in 17% of them 31,33,48–50,53 . How the dose was reported varied between the studies with 17 studies reporting median values of cisplatin administration (from 100 to 525.5 mg/m 2 ) 30,31,36,42–44,47–50,52,54–59 , and reporting mean values (from 328.2 to 425.5 mg/m 2 ) 32,38,39,45 . Seven studies only reported the range 33,37,40,46,51,53,60 , and 3 the dose per cycle 41,60,61 .…”

“…Sixty-three percent of the studies used pure-tone audiometry (PTA), of which 5 included auditory brainstem responses (ABR) 32,37,39,44,54 and 4 included distortion products of otoacoustic emissions (DPOAE) 32,37,39,40 . However, 33% did not measure hearing at baseline, which makes the changes in hearing difficult to assess 30,33,42,43,48,49,51,55,56,58 . The average percent of patients with ototoxicity (>grade 2) was 41.8%, ranging from 8 to 75%.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…Apart from genetic factors, epigenetic factors influencing cisplatin ototoxicity have recently come to attention. In a pediatric medulloblastoma and primitive neuroectodermal tumor patient cohort, Brown et al (2017) found an association between increased cisplatin ototoxicity susceptibility and a methylation locus (cg14010619) in the P21 (RAC1) Activated Kinase 4 (PAK4 gene). This gene is responsible for stereociliary bundle migration in inner and outer cochlear hair cells.…”

Using primary teeth and archived dried spots for exposomic studies in children: Exploring new paths in the environmental epidemiology of pediatric cancer

“…While it is ideal to collect samples prior to the time of diagnosis, ongoing assessments are evaluating if there are metastable epialleles related to pediatric cancer that can evaluated with samples collected at the time of diagnosis. [ 57 ] Because DNA methylation is tissue specific and is influenced by both genetic variation and environmental factors, alterations in DNA methylation may also provide mechanistic insight into treatment response and survivorship, as have been reported, [ 58,59 ] to improve clinical outcomes through epigenetic therapies in children with cancer. As noted, while a few studies have utilized DBS for epigenome‐wide assessments, to our knowledge, there have been no assessment exploring the utility of primary teeth to evaluate DNA methylation patterns, providing territory for novel explorations of pediatric cancer risk.…”