Replication of TPMT and ABCC3 Genetic Variants Highly Associated With Cisplatin-Induced Hearing Loss in Children

Abstract

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

“…Variants in COMT (rs9332377 and rs4646316) have shown similar trends of associations in four independent pediatric cohorts (Table S1) 15,23,26 . These associations reached statistical significance only in two of the four cohorts while two additional studies have also reported effect sizes in the opposite direction 25,27 .…”

“…Rednam et al reported an opposite effect of GSTP1 rs1965 on cisplatin-induced hearing loss in a pediatric medulloblastoma cohort 42 . Furthermore, five studies (4 pediatric, 1 adult) reported no significant association of GSTP1 with hearing loss 15,23,35,37,38 . Overall, evidence regarding an effect of GSTP1 rs1695 on ototoxicity is thus inconsistent (Table S4) (+ evidence).…”

“…These risk variants include the TPMT*3B, *3C and *3A (*3B + *3C) loss of function alleles, which lead to rapid degradation of the TPMT proteins 24 . In a cohort of 317 children, 43 (91.5%) carriers of the TPMT risk variant developed hearing loss compared to only four carriers (8.5%) patients without hearing loss (Table S10), conferring a specificity of 96.8% and sensitivity of 22.3% 23 . Three studies differing from the previous reports in patient cohorts and the treatment regimens used, reported non-significant associations between the TPMT variants and cisplatin-induced ototoxicity, however similar trends were observed in sub-cohorts of similarly treated patients [25][26][27] .…”

“…Specifically, TPMT variants rs12201199, rs1800460 and rs1142345 have been associated with ototoxicity in three independent pediatric cohorts 15,23 . These risk variants include the TPMT*3B, *3C and *3A (*3B + *3C) loss of function alleles, which lead to rapid degradation of the TPMT proteins 24 .…”

“…To date, two studies reported associations of a synonymous variant in ABCC3 (rs1051640) with cisplatin-induced hearing loss in pediatric patients (Table S2) 15,23 . _ENREF_31ABCC3 is a transporter that mediates the efflux of organic anions, xenobiotics and glutathione S-conjugates, including glutathione S-conjugated cisplatin 29,30 .…”