Influence of Genetic Variants in TPMT and COMT Associated with Cisplatin Induced Hearing Loss in Patients with Cancer: Two New Cohorts and a Meta-Analysis Reveal Significant Heterogeneity between Cohorts

Abstract

Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40–60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.

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

“…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] . Thus, evidence suggests an association of TPMT variants with cisplatin-induced hearing loss but with limitations in generalizability and the number of studies available (+++ evidence; Table 2).…”

“…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 . Taken together, the evidence supporting the role of COMT is encouraging but requires further replication with specific attention to using comparable patient cohorts (++ evidence).…”

Pharmacogenetic variants in TPMT alter cellular responses to cisplatin in inner ear cell lines

“…The underlying genomic variation is linked to the *3A haplotype of the TPMT gene, resulting in an 8.9 odds ratio of developing cisplatin-induced ototoxicity[13]. Since the initial replication of the TPMT-cisplatin-induced ototoxicity pharmacogenomic association[13], an independent group observed a similar association in a cohort of Spanish children[15]. By contrast, this association was not replicated in other cohorts[15, 16], that were treated with vastly different protocols compared to the original studies.…”

“…Since the initial replication of the TPMT-cisplatin-induced ototoxicity pharmacogenomic association[13], an independent group observed a similar association in a cohort of Spanish children[15]. By contrast, this association was not replicated in other cohorts[15, 16], that were treated with vastly different protocols compared to the original studies. For example, confounding treatments such as craniospinal irradiation and otoprotectant treatments (amifostine) were used for most patients, which could override genetic predispositions[17].…”

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

“…The German study by Lanvers‐Kaminsky et al. also failed to show replication of significance for both TPMT (rs12201199) and COMT (rs9332377) as did the initial Dutch cohort described by Hagleitner et al . However, in a different Spanish replication cohort described by Hagleitner et al., the same SNPs were found to be statistically significant.…”