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.

Melanie M Hagleitner,Maroeska W M Te Loo,Eveline S J M De Bont,Marieke J H Coenen,Henk-Jan Guchelaar,Peter M Hoogerbrugge,Hanneke I Vos,Hans Gelderblom,Ana Patino-Garcia,Frank N Van Leeuwen,Anna Gonzalez-Neira

doi:10.1371/journal.pone.0115869

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.

Highlights

Cisplatin is an effective chemotherapeutic drug for several types of cancer such as ovarian cancer, lung cancer, osteosarcoma and neuroblastoma
A candidate gene study in 166 pediatric patients 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 the interindividual variability [6]
The aim of the current study is to provide a clearer picture of the genetic impact of TPMT and COMT variants on developing cisplatin-induced ototoxicity

Summary

Introduction

Cisplatin is an effective chemotherapeutic drug for several types of cancer such as ovarian cancer, lung cancer, osteosarcoma and neuroblastoma. Clinical risk factors for the development of cisplatin-induced ototoxicity have been described such as age younger than 5 years at diagnosis [2, 3], concurrent medication like carboplatin [4] as well as higher cumulative doses [2, 4], cranial radiation [5] and pre-existing renal dysfunction. These clinical factors are not sufficient to reliably predict ototoxicity before the start of treatment. We investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including previously published studies [6,7,8] resulting in a total population of 664 patients with cancer

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Conclusion